Stabilized compositions of radionuclides and uses thereof

ABSTRACT

Provided herein are radiopharmaceutical compositions and uses thereof. The radiopharmaceutical compositions can comprise one or more stabilizing agents, an aqueous vehicle, and a conjugate that comprises a targeting ligand and a radionuclide bound to a metal chelator. The targeting ligand can be a small molecule compound or a peptide such as a monocyclic peptide. The targeting ligand can be configured to bind with a tumor target. The stabilizing agent can comprise a radiolysis stabilizer, a free metal chelator, and/or a pH stabilizer. Further provided herein are methods of preparing the radiopharmaceutical compositions and methods of treating cancer by administering the described radiopharmaceutical compositions.

CROSS REFERENCE

This application claims the benefit of U.S. Provisional Application No.63/228,535, filed on Aug. 2, 2021, which is incorporated herein byreference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Mar. 3, 2022, isnamed 59541-718_201_SL.txt and is 35,957 bytes in size.

BACKGROUND

In the United States, cancer is the leading cause of death for thoseunder 65 years of age, and it accounted for about 21% of all death in2018. Neuroendocrine tumors (NETs) arise from neuroendocrine cells andmost commonly develop in lung, digestive tract and pancreas. NETs areone of the cancers that need systemic therapies because either they areinoperable, or they are diagnosed at the advanced stage with distantspread of tumor cells. Traditional radiotherapies such as external beamradiation therapy have been used for decades as a standard-of-caretreatment for diagnosed cancer patients. While some patients respond toexternal beam radiation therapy, many others do not. Further, metastasisand circulating tumor cells can spread and remain in the bloodstream orbodily fluids after standard-of-care treatment and lead to resistance totherapy. The presence of cancer cells in various parts of the bodyreduces the therapeutic efficacy of traditional radiotherapies.Accordingly, strategies for targeted radiotherapies are being developedfor better cancer treatment and diagnosis. One of the major challengesin the production of radiopharmaceutical drugs is to extend theshelf-life of product to allow treatment of patients at remote locationsto the manufacturer site. There remains a need for compositions ofradionuclides, e.g., alpha-particle emitting radionuclides, that haveimproved stability and shelf lives.

SUMMARY

One of the major challenges in the production of radiopharmaceuticaldrugs is to extend the shelf-life of product to allow treatment ofpatients at remote locations to the manufacturer site. As radionuclidesuch as Actinium-225 decays, a series of highly reactive chemicals aregenerated. In some cases, they can react with the drug substance, e.g.,causing degradation of the radioisotope-containing drug and increasingradioactive impurity overtime. In one aspect, provided herein are liquidradiopharmaceutical formulations that provide enhanced stability foralpha-emitting radionuclide such as Actinium-225. In one aspect,provided herein are liquid radiopharmaceutical formulations comprising²²⁵Ac-DOTA-TATE that are stable for at least 120 hours.

In one aspect, provided herein is a liquid radiopharmaceuticalcomposition comprising: (i) a conjugate, which the conjugate is²²⁵Ac-DOTA-TATE; (ii) one or more stabilizing agents; and (iii) anaqueous vehicle.

In one aspect, provided herein is a liquid radiopharmaceuticalcomposition comprising: (i) a conjugate, which the conjugate is²²⁵Ac-DOTA-TOC; (ii) one or more stabilizing agents; and (iii) anaqueous vehicle.

In one aspect, the present disclosure relates to a liquidradiopharmaceutical composition comprising, a conjugate, optionally oneor more stabilizing agents, and an aqueous vehicle. The conjugatefurther comprises a targeting ligand, a metal chelator covalentlyattached to the targeting ligand, and a radionuclide that is bound tothe metal chelator. In some embodiments, the targeting ligand binds to asomatostatin receptor (SSR), such as a somatostatin receptor type 1(SSTR1), somatostatin receptor type 2 (SSTR2), somatostatin receptortype 3 (SSTR3), somatostatin receptor type 4 (SSTR4), and/orsomatostatin receptor type 5 (SSTR5). In some embodiments, the targetingligand binds to a somatostatin receptor type 2 (SSTR2). In someembodiments, the targeting ligand is a binding peptide, which comprises6 to 14 amino acid residues. In some embodiments, the binding peptidecomprises an amino acid sequence with at least 90% identity to asequence selected from SEQ IDs 1 to 96. In some embodiments, the bindingpeptide comprises an amino acid sequence selected from SEQ IDs 1 to 96.In some embodiments, the targeting ligand is octreotate, octreotide,D-Phe¹-cyclo(Cys²-Tyr³-D-Trp⁴-Lys⁵-Thr⁶-Cys⁷)Thr⁸ (SEQ ID NO: 97)(tyr³-octreotate or TATE),D-Phe¹-cyclo(Cys²-Tyr³-D-Trp⁴-Lys⁵-Thr⁶-Cys⁷)Thr(ol)⁸ (SEQ ID NO: 98)(Phe¹-Tyr³octreotide, edotreotide, or TOC),D-Phe¹-cyclo(Cys²-Phe³-D-Trp⁴-Lys⁵-Thr⁶-Cys⁷)Thr(ol)⁸ (SEQ ID NO: 99)(OC), D-Phe¹-cyclo(Cys²-1-Nal-D-Trp⁴-Lys⁵-Thr⁶-Cys⁷)Thr(ol)⁸ (SEQ ID NO:100) (NOC),p-Cl-Phe-cyclo(D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys)D-Tyr-NH₂) (SEQ IDNO: 101) (JR11), orp-Cl-Phe-cyclo(D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys)-D-Tyr-NH₂ (SEQ ID NO:102) (LM3). In some embodiments, the targeting ligand istyr³-octreotate, edotreotide, octreotate, or octreotide. In someembodiments, the targeting ligand is tyr³-octreotate. The targetingligand can be an agonist of the SSR. The targeting ligand can be anantagonist of the SSR. In another embodiment, the targeting ligand is asmall molecule compound, such as L-797,591, L-779,976, L-796,778,L-803,087, or L-817,818. In some embodiments, a binding affinity of thetargeting ligand to a human SSR is not more than 250 nM, not more than100 nM, not more than 50 nM, not more than 5 nM, as determined by halfmaximal inhibitory concentration (IC₅₀). In some embodiments, thebinding affinity of the targeting ligand to a human SSR is not more than250 nM, as determined by half maximal inhibitory concentration (IC₅₀).In some embodiments, the binding affinity of the targeting ligand to ahuman SSR is not more than 100 nM, as determined by half maximalinhibitory concentration (IC₅₀). In some embodiments, the bindingaffinity of the targeting ligand to a human SSR is not more than 50 nM,as determined by half maximal inhibitory concentration (IC₅₀). In someembodiments, the binding affinity of the targeting ligand to a human SSRis not more than 5 nM, as determined by half maximal inhibitoryconcentration (IC₅₀). In some embodiments, the binding affinity of thetargeting ligand to a human SSR is not more than 2 nM, as determined byhalf maximal inhibitory concentration (IC₅₀). In some embodiments, thehuman SSR is SSTR2. The targeting ligand can covalently link to themetal chelator through a linker.

In one aspect, the disclosure described herein is a radiopharmaceuticalcomposition comprising a conjugate that further comprises a targetingligand that covalently links to a metal chelator through a linker. Insome embodiments, the metal chelator is selected from AAZTA, BAT,BAT-TM, Crown, Cyclen, DO2A, CB-DO2A, DO3A, H3HP-DO3A, Oxo-DO3A,p-NH₂-Bn-Oxo-DO3A, DOTA, DOTA-3py, DOTA-PA, DOTA-GA, DOTA-4AMP,DOTA-2py, DOTA-1py, p-SCN-Bn-DOTA, CHX-A″-EDTA, MeO-DOTA-NCS EDTA,DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP,CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, NOTA, NOTP, HEHA,HEHA-NCS, p-SCN-Bn-HEHA, DTPA, CHX-A″-DTPA, p-NH₂-Bn-CHX-A″-DTPA,p-SCN-DTPA, p-SCN-Bz-Mx-DTPA, 1B4M-DTPA-DTPA, p-SCN-Bn1B-DTPA,p-SCN-Bn-1B4M-DTPA, p-SCN-Bn-CHX-A″-DTPA, PEPA, p-SCN-Bn-PEPA,1,4,8,11-tetraazacyclo tetradecane-1,4,8,11-tetrapropionic acid (TETPA),DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene-tetracarboxylic acid, macropa,macropa-NCS, macropid, H₃L¹, H₃L⁴, H₂azapa, H₅decapa, bispa², H₄pypa,H₄octapa, H₄CHXoctapa, p-SCN-Bn-H₄octapa, p-SCN-Bn-H₄octapa, TTHA,p-NO₂-Bn-neunpa, H₄octox, H₂macropa, H₂bispa², H₄phospa, H₆phospa,p-SCN-Bn-H₆phospa, TETA, p-NO₂-Bn-TETA, TRAP, TRAP-Pr, TPA, HBED, SHBED,HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, lipoic acid, TGA, BAL,Bis-thioseminarabazones, p-SCN-NOTA, nNOTA, NODAGA, CB-TE1A1P,3P-C-NETA-NCS, 3p-C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN,pycuplAiB, pycup2A, THP, DEDPA, H₂DEDPA, p-SCN-Bn-H₂DEDPA,p-SCN-Bn-TCMC, motexafin, NTA, NOC, 3p-C-NETA, p-NH₂-Bn-TE3A, SarAr,DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA,C-NE3TA-NCS, NODASA, NETA-monoamide, C-NETA, TACN-HSB, NOPO, BPCA,p-SCN-Bn-DRO, DRO-ChX-Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD,BAPEN, TACHPYR, NEC-SP, L^(py), L1, L2, L3, and EuK-106. In anotherembodiment, the metal chelator is a metal chelator in FIG. 3 to FIG. 17. In some embodiments, the metal chelator is DOTA, HEHA, or macropa. Themetal chelator can be DOTA.

In one aspect, the disclosure described herein is a radiopharmaceuticalcomposition comprising one or more stabilizing agents. The stabilizingagent can comprise a radiolysis stabilizer, which can be an amino acidor a peptide or a derivative thereof, a vitamin or a derivative thereof,a lipid or a derivative thereof, a carbohydrate or a derivative thereof,a volume expander or an antioxidant. In some embodiments, the amino acidor peptide is selected from N-Acetyl-L-cysteine, Glutathione, L-Lysine,Selenol-L-methionine, Glutathione, Albumin, Melatonin, Taurine, Alanine,Arginine, Asparagine, Aspartic acid, Cysteine, Glutamine, Glutamic acid,Glycine, Histidine, Isoleucine, Lysine, Methionine, Phenylalanine,Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine, andderivatives thereof. In some embodiments, the amino acid is Methionine.In some embodiments, the radiolysis stabilizer is an antioxidant, suchas a flavonoid or a derivative thereof. In some embodiments, theflavonoid is(2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol3-(3,4,5-trihydroxybenzoate ((−) Catechin gallate or CG),3,3′,4′,5,5′,7-Hexahydroxyflavylium chloride,(−)-cis-3,3′,4′,5,7-Pentahydroxyflavane (Epi-Catechin or EC),7-Hydroxy-3-(4′-methoxyphenyl)-4H-benzopyran-4-one,3,4,5-Trihydroxybenzoic acid (Gallic acid), 3,4′,5,7-Tetrahydroxyflavone(Kaempferol), Luteolin,2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethylloxan-2-yl]oxychromen-4-one(Rutin hydrate), Quercetin,(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl3,4,5-trihydroxybenzoate (EpiGallo-Catechin gallate or EGCg),(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoateor Epi-Catechin Gallate (ECG),(2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Epigallo-Catechin or EGC), or(2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Gallo-Catechin or GC). In some embodiments, the flavonoid is a catechinor a derivative thereof, for example,(2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((−) Catechingallate or CG), (−)-cis-3,3′,4′,5,7-Pentahydroxyflavane (Epi-Catechin orEC), 3,4,5-Trihydroxybenzoic acid (Gallic acid),(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl3,4,5-trihydroxybenzoate (EpiGallo-Catechin gallate or EGCg),(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoateor Epi-Catechin Gallate (ECG),(2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Epigallo-Catechin or EGC), or(2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Gallo-Catechin or GC). The antioxidant can also be a carotenoid or aderivative thereof, such as all-trans-Fucoxanthin, Lycopene,Xanthophyll, Beta carotene, Lycopene, or Lutein. In some embodiments,the antioxidant is N-acetyl cysteine, L-Ascorbic acid,N-tert-Butyl-α-phenylnitrone, 3-(3,4-Dihydroxyphenyl)-2-propenoic acid(Caffeic Acid), (β-Carotene, Provitamin A,(2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol3-(3,4,5-trihydroxybenzoate ((−) Catechin gallate or CG),1,4,5-Trihydroxycyclohexanecarboxylic acid, trans-4-Hydroxycinnamic acid(p-Coumaric acid), 3,3′,4′,5,5′,7-Hexahydroxyflavylium chloride,Thiocytic Acid (Dihydrolipoic Acid, DHLA),4,4′,5,5′,6,6′-Hexahydroxydiphenic acid 2,6,2′,6′-dilactone (Ellagicacid), (−)-cis-3,3′,4′,5,7-Pentahydroxyflavane (Epi-Catechin or EC),2-Methoxy-4-(2-propenyl) phenol, trans-4-Hydroxy-3-methoxycinnamic acid(Ferulic acid), 7-Hydroxy-3-(4′-methoxyphenyl)-4H-benzopyran-4-one,all-trans-Fucoxanthin, 3,4,5-Trihydroxybenzoic acid (Gallic acid),(2S,3R)-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol ((−)-Gallocatechin), Glutathione,2-(3,4-Dihydroxyphenyl)ethanol, 3,4′,5,7-Tetrahydroxyflavone(Kaempferol), (±)-1,2-Dithiolane-3-pentanoic acid, Luteolin, Lycopene,L-Lysine, Neochlorogenic acid, Oleic acid,trans-3,5,4′-Trihydroxystilbene (Resveratrol),2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one,Rutin hydrate, Selenol-L-methionine, Thiourea, (+)-α-Tocopherol,Xanthophyll, Citric acid (CA), Gentisic acid (GA), Salicylic acid (SA),Erythorbic acid (EA), Phenol, Sodium bisulfite, Butylated hydroxyanisole, Butylated hydroxy toluene, Metabisulfite, Benzyl alcohol,Thymol, Lipoic acid (LA), Thioglycolic acid (TGA), 2,3Dimercaptopropan-1-ol (BAL), Zinc, Selenium, Albumin, Ethanol, Mannitol,Sucrose, Melatonin, Ebselen, Pyruvic acid, Carboxy-PTIO, Trolox, Uricacid, Edaravone, Beta carotene, NADPH, Lycopene, Lutein, Catalase,Estrogen, Estradiol, Estriol, Ubiquinol, Copper, Quercetin, Cortisone,Taurine,(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl3,4,5-trihydroxybenzoate (EpiGallo-Catechin gallate or EGCg),(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoate or Epi-Catechin Gallate (ECG),(2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Epigallo-Catechin or EGC),(2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Gallo-Catechin or GC), (−)-Epigalocatechin-3-O-Gallate,5-Aminolevulibic Acid hydrate, Ploysorbate 80, Garlic Acid, SodiumL-Ascorbate, Hyaluronic Acid, Dextran 60-90, Selenol, and LysaKare. Theradiolysis stabilizer can also be a vitamin or a derivative thereof, forexample, L-Ascorbic acid, β-Carotene, Provitamin A, (+)-α-Tocopherol,Erythorbic acid (EA), Trolox, and Lutein. In some embodiments,radiolysis stabilizer is a lipid. The lipid can be a fatty acid, such asa saturated or unsaturated C₆ to C₃₀ fatty acid. In some embodiments,the fatty acid is oleic acid, Myristoleic acid, Palmitoleic acid,Sapienic acid, Elaidic acid, Vaccenic acid, or Linoleic acid,α-Linolenic acid. In another embodiment, the lipid is a steroid orderivatives thereof, for example, Estrogen, Estradiol, Estriol, orCortisone. The radiolysis stabilizer can also be a carbohydrate or aderivative thereof, such as Mannitol, Sucrose, Dextran (e.g., Dextran40, Dextran 70), and Cyclodextrins, (e.g., a (alpha)-cyclodextrin,β(beta)-cyclodextrin, and γ (gamma)-cyclodextrin). In some embodiments,the radiolysis stabilizer is a volume expander. The volume expander canbe a polymer or a polymer mixture, such as PEG 3350, PEG 4000,Polygeline, Haemaccel, Gelofusine, and PLENVU (polyethylene glycol 3350,sodium sulfate, ascorbic acid, sodium chloride and potassium chloride USFDA 2018 Label). In some embodiments, volume expander is selected fromDextran, Dextran 40, Dextran 70, Cyclodextrins, α (alpha)-cyclodextrin,β (beta)-cyclodextrin, and γ (gamma)-cyclodextrin, PEG 3350, PEG 4000,Polygeline, Gelofusine, and PLENVU (polyethylene glycol 3350, sodiumsulfate, ascorbic acid, sodium chloride and potassium chloride US FDA2018 Label). In some embodiments, radiolysis stabilizer is selected fromN-Acetyl-L-cysteine, L-Ascorbic acid, N-tert-Butyl-α-phenylnitrone,3-(3,4-Dihydroxyphenyl)-2-propenoic acid (Caffeic Acid), β-Carotene,Provitamin A,(2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol3-(3,4,5-trihydroxybenzoate ((−) Catechin gallate, or CG),1,4,5-Trihydroxycyclohexanecarboxylic acid, trans-4-Hydroxy cinnamicacid (p-Coumaric acid), 3,3′,4′,5,5′,7-Hexahydroxyflavylium chloride,Thiocytic Acid (Dihydrolipoic Acid, DHLA),4,4′,5,5′,6,6′-Hexahydroxydiphenic acid 2,6,2′,6′-dilactone (Ellagicacid), (−)-cis-3,3′,4′,5,7-Pentahydroxyflavane (Epi-Catechin or EC),2-Methoxy-4-(2-propenyl) phenol, trans-4-Hydroxy-3-methoxycinnamic acid(Ferulic acid), 7-Hydroxy-3-(4′-methoxyphenyl)-4H-benzopyran-4-one,all-trans-Fucoxanthin, 3,4,5-Trihydroxybenzoic acid (Gallic acid),(2S,3R)-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol((−)-Gallocatechin), Glutathione, 2-(3,4-Dihydroxyphenyl)ethanol,3,4′,5,7-Tetrahydroxyflavone (Kaempferol),(±)-1,2-Dithiolane-3-pentanoic acid, Luteolin, Lycopene, L-Lysine,Neochlorogenic acid, Oleic acid, trans-3,5,4′-Trihydroxystilbene(Resveratrol),2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one,Rutin hydrate, Selenol-L-methionine, Thiourea, (+)-α-Tocopherol,Xanthophyll, Alanine and its derivatives, Arginine and its derivatives,Asparagine and its derivatives, Aspartic acid and its derivatives,Cysteine and its derivatives, Glutamine and its derivatives, Glutamicacid and its derivatives, Glycine and its derivatives, Histidine and itsderivatives, Isoleucine and its derivatives, Lysine and its derivatives,Methionine and its derivatives, Phenylalanine and its derivatives,Proline and its derivatives, Serine and its derivatives, Threonine andits derivatives, Tryptophan and its derivatives, Tyrosine and itsderivatives, Valine and its derivatives, Citric acid (CA), Gentisic acid(GA), Salicylic acid (SA), Erythorbic acid (EA), Phenol, Sodiumbisulfite, Butylated hydroxy anisole, Butylated hydroxy toluene,Glutathione, Metabisulfite, Benzyl alcohol, Thymol, Lipoic acid (LA),Thioglycolic acid (TGA), 2,3 Dimercaptopropan-1-ol (BAL), Zinc,Selenium, Albumin, Ethanol, Mannitol, Sucrose, Melatonin, Ebselen,Pyruvic acid, Carboxy-PTIO, Trolox, Uric acid, Edaravone, Beta carotene,NADPH, Lycopene, Lutein, Catalase, Estrogen, Estradiol, Estriol,Ubiquinol, Copper, Quercetin, Cortisone, 2,3-dimercaptosuccinic acid(DMSA), monisoamyl derivative (MiADMSA), Taurine, Dextran, Dextran 40,Dextran 70, PEG 3350, PEG 4000, Polygeline, Gelofusine, PLENVU(polyethylene glycol 3350, sodium sulfate, ascorbic acid, sodiumchloride and potassium chloride US FDA 2018 Label), Cyclodextrins, α(alpha)-cyclodextrin, β (beta)-cyclodextrin, and γ (gamma)-cyclodextrin,(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl3,4,5-trihydroxybenzoate (EpiGallo-Catechin gallate or EGCg),(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoate or Epi-Catechin Gallate (ECG),(2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Epigallo-Catechin or EGC),(2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Gallo-Catechin or GC).

In one aspect, disclosed herein is a radiopharmaceutical compositioncomprising one or more stabilizing agents that further comprise a firstand a second radiolysis stabilizer. In some embodiments, the first andthe second radiolysis stabilizer has a molar ratio that is from 1:5 to5:1. In some embodiments, radiolysis stabilizer is present in theradiopharmaceutical composition at about 0.01 mM to about 5 M. In someembodiments, the stabilizing agent is present in the radiopharmaceuticalcomposition from about 5 mM, 10 mM, 25 mM, 50 mM, or 75 mM to about 80mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 250 mM, or 500 mM. In someembodiments, stabilizing agent is present in the radiopharmaceuticalcomposition at about 0.1 mM to about 500 mM. In some embodiments, thestabilizing agent is present in the radiopharmaceutical composition atabout 10 mM to about 500 mM. In some embodiments, the stabilizing agentis present in the radiopharmaceutical composition at about 20 mM toabout 100 mM. In some embodiments, the radiolysis stabilizer is presentin the radiopharmaceutical composition at about 0.0001 wt % to about 10wt %. In some embodiments, the radiolysis stabilizer is present in theradiopharmaceutical composition at about 0.01 wt % to about 5 wt %,about 0.05 wt % to about 2 wt %, or about 0.1 wt % to about 1 wt %. Insome embodiments, the radiolysis stabilizer is present in theradiopharmaceutical composition at a concentration of from about 0.1 to50 mg/mL. In some embodiments, the volume expander is present in theradiopharmaceutical composition at a concentration of from about 0.001wt % to 80% wt %.

In one aspect, disclosed herein is a radiopharmaceutical compositioncomprising one or more stabilizing agent that can comprise a free metalchelator, which is not attached to the targeting ligand. In someembodiments, the free metal chelator is selected fromEthylenediaminetetraacetic acid (EDTA), Diethylenetriaminepentaaceticacid (DTPA),2-S-(4-Isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triaceticacid (NOTA), Triethylenetetramine (TETA), 1, 4, 7, 10,13-pentaazacyclopentadecane-N, N′, N″, N′″, N″″-pentaacetic acid (PEPA),1,4,8,11-tetraazacyclo tetradecane-1,4,8,11-tetrapropionic acid (TETPA),triethylenetetraminepentaacetic acid,2,2′,2″-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triaceticacid (DOTA-GA), 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid (DOTP), Deferoxamine (DFO), N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED),1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid)(DOTP),6,6′-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinicacid (Macropa), Meso-2,3-dimercaptosuccinic acid (DMSA),Dimercaptopropane sulfonate (DMPS), Dihydrolipoic acid (DHLA), Lipoicacid (LA), Thioglycolic acid (TGA), 2,3 Dimercaptopropan-1-ol (BAL). Insome embodiments, the free metal chelator is EDTA, DTPA, or Macropa. Insome embodiments, the free metal chelator is present in theradiopharmaceutical composition at about 0.001 wt % to about 10 wt %. Insome embodiments, the free metal chelator is present in theradiopharmaceutical composition at about 0.01 wt % to about 5 wt %,about 0.05 wt % to about 2 wt %, or about 0.1 wt % to about 1 wt %. Insome embodiments, the free metal chelator is present in theradiopharmaceutical composition at a concentration of from 0.01 to 50mg/mL. In some embodiments, the free metal chelator is present in theradiopharmaceutical composition at about 10 mM to about 500 mM.

In one aspect, disclosed herein is a radiopharmaceutical compositioncomprising one or more stabilizing agent that can comprise one or morepH stabilizers. The pH stabilizers can function as a pH buffer. The oneor more pH stabilizers comprise an organic acid, such as an acetic acid,fumaric acid, ascorbic acid, propionic acid, benzene sulfonic acid,carbonic acid, citrate acid, aspartic acid, maleic acid, methanesulfonic acid, or tartaric acid. In some embodiments, the one or more pHstabilizers comprise an inorganic acid, for example, hydrobromic acid,hydrochloric acid, phosphoric acid, boric acid, or sulfuric acid. Theone or more pH stabilizers can comprise a base, such as tromethamine(Tris), ammonium hydroxide, diethanolamine, or sodium hydroxide. The oneor more pH stabilizers can also comprise an amino acid or a saltthereof. In some embodiments, the amino acid is glycine, lysine,arginine, histidine, or a salt thereof. In another embodiment, the oneor more pH stabilizers comprise an alkaline salt, for example, sodiumacetate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodiumcarbonate, tribasic sodium phosphate acid, dibasic sodium phosphateacid, monobasic sodium phosphate acid, sodium tartrate, sodium lactate,sodium succinate, or disodium succinate. The one or more pH stabilizerscan comprise an acid salt, such as ammonium sulfate. In someembodiments, the one or more pH stabilizers comprise Sodium acetate,Sodium ascorbate, Ascorbic acid, Acetic acid, Fumaric acid propionicacid, ascorbic acid, ammonium sulfate, ammonium hydroxide, arginine,aspartic acid, benzene sulfonic acid, sodium benzoate, sodiumbicarbonate, boric acid, sodium carbonate, carbonic acid,diethanolamine, citrate acid, hydrobromic acid, glycine, histidine,sodium lactate, (l)-lysine, maleic acid, methane sulfonic acid,phosphate acid, monobasic sodium phosphate acid, tribasic sodiumphosphate acid, dibasic sodium phosphate acid, sodium hydroxide,sodium/disodium succinate, sulfuric acid, sodium tartrate, tartaricacid, tromethamine (tris), or a combination thereof. In someembodiments, the one or more pH stabilizers are present in theradiopharmaceutical composition at about 0.001 wt % to about 10 wt %. Insome embodiments, one or more pH stabilizers are present in theradiopharmaceutical composition at about 0.01 wt % to about 5 wt %,about 0.05 wt % to about 2 wt %, or about 0.1 wt % to about 1 wt %. Insome embodiments, the one or more pH stabilizers are present in theradiopharmaceutical composition at a concentration of from 0.1 to 5mg/mL. In some embodiments, the one or more pH stabilizers are presentin the radiopharmaceutical composition at about 10 mM to about 500 mM.The one or more pH stabilizers can be configured to maintain a pH of theradiopharmaceutical composition at about 4 to about 8. The one or morepH stabilizers can be configured to maintain a pH of theradiopharmaceutical composition at about 5 to about 7. In someembodiments, the pH of the radiopharmaceutical composition is within arange of about 4 to about 8. In some embodiments, the pH of theradiopharmaceutical composition is about 5.5 to about 6.0. Theradiopharmaceutical composition can comprise one or more radiolysisstabilizers, one or more free metal chelators, and/or one or more pHstabilizers.

In one aspect, disclosed herein is a radiopharmaceutical compositioncomprising an aqueous vehicle. The aqueous vehicle can comprise water(e.g., water for injection), saline solution, dextrose in water,dextrose in saline solution, Ringer's solution, or lactated Ringer'ssolution. The radiopharmaceutical composition can be isotonic. Theradiopharmaceutical composition can be a solution or suspension. In someembodiments, the radiopharmaceutical composition is formulated for IVinfusion or bolus injection. In some embodiments, theradiopharmaceutical composition further comprises one or more excipientsselected from: a tonicity adjusting agent, a preservative, anantimicrobial agent, a solubilizing agent, a suspending agent, and asurfactant.

In one aspect, disclosed herein is a radiopharmaceutical compositioncomprising a conjugate that further comprises a targeting ligand thatcovalently links to a metal chelator through a linker. In someembodiments, the targeting ligand is a binding peptide, and the linkeris attached to the binding peptide via the N terminus of the peptide. Insome embodiments, the targeting ligand is a binding peptide, and thelinker is attached to the binding peptide via the C terminus of thepeptide. In some embodiments, the targeting ligand is a binding peptide,and the linker is attached to the binding peptide via a non-terminalamino acid of the peptide. The linker can comprise one or more groupsselected from: substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.

In one aspect, disclosed herein is a radiopharmaceutical compositioncomprising a conjugate that further comprises a radionuclide. Theradionuclide can be an alpha particle-emitting radionuclide, such asactinium-225, astatine-211, thorium-227, or radium-223. In someembodiments, the alpha particle-emitting radionuclide is actinium-225.In some embodiments, the actinium-225 is present in theradiopharmaceutical composition that it provides a volumetricradioactivity of about 0.5 to 20 MBq/mL. In some embodiments, theconjugate is ²²⁵Ac-DOTATATE. In another embodiment, the conjugate is²²⁵Ac-DOTATOC. In some embodiments, the radiopharmaceutical compositionretains at least 90 mol % of the initial conjugate after 168 hours atroom temperature (25° C.). In some embodiments, the composition retainsat least 95 mol % of the initial conjugate after 168 hours at roomtemperature (25° C.). In some embodiments, the composition retains atleast 98 mol % of the initial conjugate after 168 hours at roomtemperature (25° C.). In some embodiments, the composition retains atleast 85 mol %, at least 90 mol %, at least 92 mol %, at least 95 mol %,at least 98 mol % or at least 99 mol % of the initial conjugate after120 hours at room temperature (25° C.). In some embodiments, thecomposition retains 95 mol % or more of the initial conjugate after 48hours, 72 hours, 96 hours, 120 hours, 148 hours, 168 hours, 192 hours,or 216 hours at room temperature (25° C.). In some embodiments, theradionuclide is actinium-225, and wherein the composition contains nomore than about 5% free actinium after 168 hours at room temperature(25° C.), compared to the total amount of the initial chelated actiniumcontent in the composition. In some embodiments, the radionuclide isactinium-225, and wherein the composition contains no more than about 2%or about 1% free actinium after 168 hours at room temperature (25° C.),compared to the total amount of the initial chelated actinium content inthe composition. In some embodiments, the radionuclide is actinium-225,and wherein the composition contains no more than a total of 5 mol % offree daughter isotopes of actinium-225 after 168 hours at roomtemperature (25° C.), compared to the total amount of the initialchelated actinium content in the composition. In some embodiments, theradionuclide is actinium-225, and wherein the composition contains nomore than a total of 1 mol % of un-chelated daughter isotopes ofactinium-225 after 168 hours at room temperature (25° C.), compared tothe total amount of the initial chelated actinium content in thecomposition. In some embodiments, the purity or the molar percentage ofthe initial conjugate is determined by radio thin layer chromatography(radio-TLC). In some embodiments, the purity or the molar percentage ofthe initial conjugate is determined by instant thin layer chromatography(iTLC).

In one aspect, the present disclosure relates to a method of making aradiopharmaceutical composition described herein. In some embodiments,the method of making the radiopharmaceutical composition comprisescombining a radionuclide (such as ²²⁵Ac) with a pre-labeled conjugate(e.g., DOTATATE or DOTATOC) in the presence of one or more stabilizeragents, wherein the pre-labeled conjugate comprises a targeting ligandand a metal chelator covalently attached to the targeting ligand,thereby producing a mixture comprising a labeled conjugate (e.g.,²²⁵Ac-DOTATATE or ²²⁵Ac-DOTATOC), and optionally combining one or morestabilizing agents to the mixture. In some embodiments, the method ofmaking the radiopharmaceutical composition comprises combining aradionuclide (such as ²²⁵Ac) with a pre-labeled conjugate (e.g.,DOTATATE or DOTATOC), wherein the pre-labeled conjugate comprises atargeting ligand and a metal chelator covalently attached to thetargeting ligand, thereby producing a labeled conjugate, and combiningthe one or more stabilizing agents with the labeled conjugate.

In one aspect, the present disclosure relates to a method of treating adisease in a subject in need thereof, comprising administering to thesubject the radiopharmaceutical composition described herein. Thedisease can be a cancer. In some embodiments, the cancer is anSSR-associated cancer, such as an SSTR2-associated cancer. The cancercan be a neuroendocrine cancer, a lymphatic cancer, a pancreatic cancer,a pituitary cancer, a breast cancer, a stomach cancer, medulloblastoma,or neuroblastoma. In some embodiments, the cancer is a neuroendocrinecancer, which can optionally be recurrent. In some embodiments, theneuroendocrine cancer is refractory to a radiotherapy that comprisesbeta-particle emitting radionuclide. In some embodiments, the subjecthas received a radiotherapy that comprises beta-particle emittingradionuclide prior to the administering of the radiopharmaceuticalcomposition. The neuroendocrine cancer can also be a neuroendocrine lungcancer or a neuroendocrine pancreatic cancer. In some embodiments, theneuroendocrine cancer is a Carcinoid tumor in the lungs,gastrointestinal tract or thymus, Pancreatic neuroendocrine tumor (e.g.,Gastrinoma, Insulinoma, Glucagonoma, VIPoma) Medullary thyroidcarcinoma, Merkel cell carcinoma, Pheochromocytoma of the adrenal gland,Adrenal cancer, Small cell carcinoma (such as in the lungs), or Largecell carcinoid tumor (such as in the lungs). In some embodiments, theradiopharmaceutical composition is administered to the subject in anamount equivalent to about 1 kBq/kg to about 0.2 GBq/kg body weight perdose. In some embodiments, the radiopharmaceutical composition isadministered to the subject in an amount equivalent to about 5 kBq/kg toabout 50,000 kBq/kg body weight per dose. In some embodiments, theradiopharmaceutical composition is administered to the subject in anamount equivalent to about 20 kBq/kg to about 5,000 kBq/kg body weightper dose. In some embodiments, the radiopharmaceutical composition isadministered to the subject in an amount equivalent to about 50 kBq/kgto about 500 kBq/kg body weight per dose. In some embodiments, theradiopharmaceutical composition is administered to the subject in anamount equivalent to about 50 kBq/kg to about 200 kBq/kg body weight perdose. In some embodiments, the radiopharmaceutical composition isadministered to the subject in an amount equivalent to about 70 kBq/kgto about 150 kBq/kg body weight per dose. In some embodiments, theradiopharmaceutical composition is administered at an 8-week interval.In some embodiments, the radiopharmaceutical composition is administeredto achieve a cumulative dose in the subject of about 10,000 kBq to about100,000 kBq. In some embodiments, the radiopharmaceutical composition isadministered to achieve a cumulative dose in the subject of about 40,000kBq to about 70,000 kBq.

In one aspect, provided herein is a dilution solution comprising one ormore stabilizing agents and an aqueous vehicle.

In one aspect, provided herein is a liquid radiopharmaceuticalcomposition comprising: (a) ²²⁵Ac-DOTA-TATE, wherein the ²²⁵Ac-DOTA-TATEis present in the radiopharmaceutical composition at a concentrationequivalent to about 10 mCi/L to about 30 mCi/L; (b) sodium L-ascorbate,wherein the sodium L-ascorbate is present in the radiopharmaceuticalcomposition at a concentration of about 80 mM to about 110 mM; (c)diethylenetriamine pentaacetate (DTPA), wherein the DTPA is present inthe radiopharmaceutical composition at a concentration of about 0.04mg/mL to about 0.06 mg/mL; and (d) an aqueous vehicle, wherein theaqueous vehicle is sodium chloride saline solution at a concentration ofabout 0.9% w/w; wherein the radiopharmaceutical composition is asolution, and wherein the radiopharmaceutical composition retains atleast 90% of the ²²⁵Ac content as ²²⁵Ac-DOTA-TATE after 120 hours atabout 20° C. to about 25° C. as determined by radio thin-layerchromatography (radio-TLC). In one aspect, provided herein is a liquidradiopharmaceutical composition consisting essentially of:(a)²²⁵Ac-DOTA-TATE, wherein the ²²⁵Ac-DOTA-TATE is present in theradiopharmaceutical composition at a concentration equivalent to about10 mCi/L to about 30 mCi/L; (b) sodium L-ascorbate, wherein the sodiumL-ascorbate is present in the radiopharmaceutical composition at aconcentration of about 80 mM to about 110 mM; (c) diethylenetriaminepentaacetate (DTPA), wherein the DTPA is present in theradiopharmaceutical composition at a concentration of about 0.04 mg/mLto about 0.06 mg/mL; and (d) an aqueous vehicle, wherein the aqueousvehicle is sodium chloride saline solution at a concentration of about0.9% w/w; wherein the radiopharmaceutical composition is a solution, andwherein the radiopharmaceutical composition retains at least 90% of the²²⁵Ac content as ²²⁵Ac-DOTA-TATE after 120 hours at about 20° C. toabout 25° C. as determined by radio thin-layer chromatography(radio-TLC). In one aspect, provided herein is a liquidradiopharmaceutical composition consisting of: (a)²²⁵Ac-DOTA-TATE,wherein the ²²⁵Ac-DOTA-TATE is present in the radiopharmaceuticalcomposition at a concentration equivalent to about 10 mCi/L to about 30mCi/L; (b) sodium L-ascorbate, wherein the sodium L-ascorbate is presentin the radiopharmaceutical composition at a concentration of about 90 mMto about 110 mM; (c) diethylenetriamine pentaacetate (DTPA), wherein theDTPA is present in the radiopharmaceutical composition at aconcentration of about 0.04 mg/mL to about 0.06 mg/mL; and (d) anaqueous vehicle, wherein the aqueous vehicle is sodium chloride salinesolution at a concentration of about 0.9% w/w; wherein theradiopharmaceutical composition is a solution, and wherein theradiopharmaceutical composition retains at least 90% of the ²²⁵Accontent as ²²⁵Ac-DOTA-TATE after 120 hours at about 20° C. to about 25°C. as determined by radio thin-layer chromatography (radio-TLC). In someembodiments, the ²²⁵Ac-DOTA-TATE is present in the radiopharmaceuticalcomposition at a concentration equivalent to about 10 mCi/L to about 25mCi/L. In some embodiments, the ²²⁵Ac-DOTA-TATE is present in theradiopharmaceutical composition at a concentration equivalent to about12 mCi/L to 23 mCi/L. In some embodiments, the ²²⁵Ac-DOTA-TATE ispresent in the radiopharmaceutical composition at a concentrationequivalent to about 40 μg to about 120 μg of the DOTA-TATE. In someembodiments, the sodium ascorbate is present in the radiopharmaceuticalcomposition at a concentration of about 100 mM. In some embodiments, theDTPA is present in the radiopharmaceutical composition at aconcentration of about 0.05 mg/mL. In some embodiments, the compositionretains at least 90% of the ²²⁵Ac content as ²²⁵Ac-DOTA-TATE after 168hours at about 20° C. to about 25° C. In some embodiments, thecomposition retains at least 90% of the ²²⁵Ac content as ²²⁵Ac-DOTA-TATEafter 192 hours at about 20° C. to about 25° C. In some embodiments, theradiopharmaceutical composition is formulated as a unit dose form thatcontains about 12 mL of the solution, and wherein the liquidradiopharmaceutical composition consists of: (a) ²²⁵Ac-DOTA-TATE presentin the radiopharmaceutical composition in an amount of 146-275 μCi inthe about 12 mL solution; (b) sodium L-ascorbate present in theradiopharmaceutical composition at a concentration of about 18.5 mg/mL;(c) DTPA, present in the radiopharmaceutical composition at aconcentration of about 0.05 mg/mL; and (d) sodium chloride salinesolution at a concentration of about 0.9% w/w. In some embodiments, theliquid radiopharmaceutical composition has a pH of about 5.5 to about7.0. In some embodiments, the radiopharmaceutical composition isformulated for IV infusion.

In one aspect, provided herein is a liquid radiopharmaceuticalcomposition wherein the ²²⁵Ac-DOTA-TATE has a structure illustrated as:

In one aspect, provided herein is a method of treating a somatostatinreceptor-positive (SSTR+) neuroendocrine tumor in a subject in needthereof, comprising administering to the subject an effective amount ofa liquid radiopharmaceutical composition, wherein the liquidradiopharmaceutical composition comprises: (a)²²⁵Ac-DOTA-TATE, whereinthe ²²⁵Ac-DOTA-TATE is present in the radiopharmaceutical composition ata concentration equivalent to about 10 mCi/L to about 30 mCi/L; (b)sodium L-ascorbate, wherein the sodium L-ascorbate is present in theradiopharmaceutical composition at a concentration of about 90 mM toabout 110 mM; (c) diethylenetriamine pentaacetate (DTPA), wherein theDTPA is present in the radiopharmaceutical composition at aconcentration of about 0.04 mg/mL to about 0.06 mg/mL; and (d) anaqueous vehicle, wherein the aqueous vehicle is sodium chloride salinesolution at a concentration of about 0.9% w/w; wherein theradiopharmaceutical composition is a solution, and wherein theradiopharmaceutical composition retains at least 90% of the ²²⁵Accontent as ²²⁵Ac-DOTA-TATE after 120 hours at about 20° to about 25° C.as determined by radio thin-layer chromatography (radio-TLC).

In one aspect, provided herein is a method of treating a somatostatinreceptor-positive (SSTR+) neuroendocrine tumor in a subject in needthereof, comprising administering to the subject an effective amount ofa liquid radiopharmaceutical composition, wherein the liquidradiopharmaceutical composition consists essentially of:(a)²²⁵Ac-DOTA-TATE, wherein the ²²⁵Ac-DOTA-TATE is present in theradiopharmaceutical composition at a concentration equivalent to about10 mCi/L to about 30 mCi/L; (b) sodium L-ascorbate, wherein the sodiumL-ascorbate is present in the radiopharmaceutical composition at aconcentration of about 90 mM to about 110 mM; (c) diethylenetriaminepentaacetate (DTPA), wherein the DTPA is present in theradiopharmaceutical composition at a concentration of about 0.04 mg/mLto about 0.06 mg/mL; and (d) an aqueous vehicle, wherein the aqueousvehicle is sodium chloride saline solution at a concentration of about0.9% w/w; wherein the radiopharmaceutical composition is a solution, andwherein the radiopharmaceutical composition retains at least 90% of the²²⁵Ac content as ²²⁵Ac-DOTA-TATE after 120 hours at about 20° to about25° C. as determined by radio thin-layer chromatography (radio-TLC).

In one aspect, provided herein is a method of treating a somatostatinreceptor-positive (SSTR+) neuroendocrine tumor in a subject in needthereof, comprising administering to the subject an effective amount ofa liquid radiopharmaceutical composition, wherein the liquidradiopharmaceutical composition consists of: (a) ²²⁵Ac-DOTA-TATE,wherein the ²²⁵Ac-DOTA-TATE is present in the radiopharmaceuticalcomposition at a concentration equivalent to about 10 mCi/L to about 30mCi/L; (b) sodium L-ascorbate, wherein the sodium L-ascorbate is presentin the radiopharmaceutical composition at a concentration of about 90 mMto about 110 mM; (c) diethylenetriamine pentaacetate (DTPA), wherein theDTPA is present in the radiopharmaceutical composition at aconcentration of about 0.04 mg/mL to about 0.06 mg/mL; and (d) anaqueous vehicle, wherein the aqueous vehicle is sodium chloride salinesolution at a concentration of about 0.9% w/w; wherein theradiopharmaceutical composition is a solution, and wherein theradiopharmaceutical composition retains at least 90% of the ²²⁵Accontent as ²²⁵Ac-DOTA-TATE after 120 hours at about 20° to about 25° C.as determined by radio thin-layer chromatography (radio-TLC). In someembodiments, the neuroendocrine tumor is gastroenteropancreaticneuroendocrine tumor (GEP-NET). In some embodiments, the subjectreceived ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC treatment prior to theadministrating of the liquid radiopharmaceutical composition. In someembodiments, prior to the administrating of the liquidradiopharmaceutical composition, the subject received ¹⁷⁷Lu-DOTA-TATE or¹⁷⁷Lu-DOTA-TOC treatment and the tumor has progressed. In someembodiments, the radiopharmaceutical composition is administered to thesubject in an amount equivalent to about 60 kBq/kg body weight to 120kBq/kg body weight per dose. In some embodiments, theradiopharmaceutical composition is administered at an 8-week interval.In some embodiments, the ²²⁵Ac-DOTA-TATE is present in theradiopharmaceutical composition at a concentration equivalent to about10 mCi/L to about 25 mCi/L.

In one aspect, provided herein is a method of treating a somatostatinreceptor-positive (SSTR+) neuroendocrine tumor in a subject in needthereof, comprising administering to the subject an effective amount ofa liquid radiopharmaceutical composition, wherein the liquidradiopharmaceutical composition consists of: (a) ²⁵Ac-DOTA-TATE presentin the radiopharmaceutical composition at a concentration equivalent to10 mCi/L to 25 mCi/L; (b) sodium L-ascorbate present in theradiopharmaceutical composition at a concentration of about 100 mM; (c)DTPA, present in the radiopharmaceutical composition at a concentrationof about 0.05 mg/mL; and (d) sodium chloride saline solution at aconcentration of about 0.9% w/w.

In one aspect, provided herein is a method of treating a somatostatinreceptor-positive (SSTR+) neuroendocrine tumor in a subject in needthereof, comprising administering to the subject an effective amount ofa liquid radiopharmaceutical composition, wherein the liquidradiopharmaceutical composition is formulated as a unit dose form thathas about 12 mL of the solution, and wherein the liquidradiopharmaceutical composition consists of: (a) ²²⁵Ac-DOTA-TATE presentin the radiopharmaceutical composition in an amount of 146-275 μCi inabout 12 mL solution; (b) sodium L-ascorbate present in theradiopharmaceutical composition at a concentration of about 18.5 mg/mL;(c) DTPA present in the radiopharmaceutical composition at aconcentration of about 0.05 mg/mL; and (d) sodium chloride salinesolution at a concentration of about 0.9% w/w.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference for the specificpurposes identified herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the disclosure are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present disclosure will be obtained by reference tothe following detailed description that sets forth illustrativeembodiments, in which the principles of the disclosure are utilized, andthe accompanying drawing (also “figure” and “FIG.” herein), of which:

FIG. 1A depicts the structures of exemplary radiolysis stabilizerscatechins and their derivatives; FIG. 1B illustrates the structures ofexemplary stabilizing agents cyclodextrin; FIG. 1C illustrates thestructures of exemplary stabilizing agents (antioxidants); FIG. 1Dillustrates the structures of exemplary stabilizing agents (aminoacids); and FIG. 1E illustrates the structures of exemplary stabilizingagents.

FIG. 2A illustrates the structures of exemplary small molecule targetingligands; FIG. 2B illustrates the structures of exemplary bindingpeptide.

FIG. 3 -FIG. 17 depict the structures of representative metal chelators.

FIG. 18A and FIG. 18B illustrate the abbreviations and modification ofamino acids.

FIG. 19 depicts a clinical treatment dosing schedule using²²⁵Ac-DOTA-TATE. Patients receive a de-escalating dose scheme and willreceive up to 4 cycles of ²²⁵Ac-DOTA-TATE every 8 weeks.

DETAILED DESCRIPTION

The following description and examples illustrate embodiments of thepresent disclosure in detail. It is to be understood that this presentdisclosure is not limited to the particular embodiments described hereinand as such can vary. Those of skill in the art will recognize thatthere are numerous variations and modifications of this presentdisclosure, which are encompassed within its scope.

Although various features of the present disclosure may be described inthe context of a single embodiment, the features may also be providedseparately or in any suitable combination. Conversely, although thepresent disclosure may be described herein in the context of separateembodiments for clarity, the present disclosure may also be implementedin a single embodiment.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

All terms are intended to be understood as they would be understood by aperson skilled in the art. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which the disclosurepertains.

The following definitions supplement those in the art and are directedto the current application and are not to be imputed to any related orunrelated case, e.g., to any commonly owned patent or application.Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice for testing of the presentdisclosure, the preferred materials and methods are described herein.Accordingly, the terminology used herein is for the purpose ofdescribing particular embodiments only and is not intended to belimiting.

I. Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “an agent” includes aplurality of such agents, and reference to “the cell” includes referenceto one or more cells (or to a plurality of cells) and equivalentsthereof known to those skilled in the art, and so forth. When ranges areused herein for physical properties, such as molecular weight, orchemical properties, such as chemical formulae, all combinations andsubcombinations of ranges and specific embodiments therein are intendedto be included.

The term “about” or “approximately” can mean within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” can mean within 1 or more than 1 standard deviation,per the practice in the art. Alternatively, “about” can mean a range ofup to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value.Alternatively, particularly with respect to biological systems orprocesses, the term can mean within an order of magnitude, within5-fold, or within 2-fold, of a value.

The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, “consist of” or “consist essentially of” the describedfeatures.

“Radiolysis” refers to the decay of radionuclides accompanied byemission of energy in the form of alpha, beta and/or gamma radiations.The energy that goes into the drug-containing formulation can breakchemical bonds and can generate reactive chemical species from solventmolecules, which may further decompose the radiopharmaceutical drugdirectly and/or indirectly.

“Amino” refers to the —NH2 radical.

“Nitro” refers to the —NO2 radical.

“Oxo” refers to the ═O radical.

“Imino” refers to the ═N—H radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Alkyl” refers to an optionally substituted straight-chain, oroptionally substituted branched-chain saturated hydrocarbon monoradical.An alkyl group can have from one to about twenty carbon atoms, from oneto about ten carbon atoms, or from one to six carbon atoms. Examplesinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl,and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like.Whenever it appears herein, a numerical range such as “C₁-C₆ alkyl”means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, althoughthe present definition also covers the occurrence of the term “alkyl”where no numerical range is designated. In some embodiments, the alkylis a C₁-C₁₀ alkyl, a C₁-C₉ alkyl, a C₁-C₈ alkyl, a C₁-C₇ alkyl, a C₁-C₆alkyl, a C₁-C₅ alkyl, a C₁-C₄ alkyl, a C₁-C₃ alkyl, a C₁-C₂ alkyl, or aC₁ alkyl. Unless stated otherwise specifically in the specification, analkyl group is optionally substituted, for example, with oxo, halogen,amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, thealkyl is optionally substituted with oxo, halogen, —CN, —CF₃, —OH, —OMe,—NH₂, —NO₂, or —C≡CCH. In some embodiments, the alkyl is optionallysubstituted with oxo, halogen, —CN, —CF₃, —OH, or —OMe. In someembodiments, the alkyl is optionally substituted with halogen.

The term “aryl” refers to a radical comprising at least one aromaticring wherein each of the atoms forming the ring is a carbon atom. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, and naphthyl. In some embodiments, thearyl is phenyl. Depending on the structure, an aryl group can be amonoradical or a diradical (i.e., an arylene group). Unless statedotherwise specifically in the specification, the term “aryl” or theprefix “ar-” (such as in “aralkyl”) is meant to include aryl radicalsthat are optionally substituted. In some embodiments, an aryl groupcomprises a partially reduced cycloalkyl group defined herein (e.g.,1,2-dihydronaphthalene). In some embodiments, an aryl group comprises afully reduced cycloalkyl group defined herein (e.g.,1,2,3,4-tetrahydronaphthalene). When aryl comprises a cycloalkyl group,the aryl is bonded to the rest of the molecule through an aromatic ringcarbon atom. An aryl radical can be a monocyclic or polycyclic (e.g.,bicyclic, tricyclic, or tetracyclic) ring system, which may includefused, spiro or bridged ring systems. Unless stated otherwisespecifically in the specification, an aryl may be optionallysubstituted, for example, with halogen, amino, alkylamino, aminoalkyl,nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,—S(O)₂NH—C₁-C₆alkyl, and the like. In some embodiments, an aryl isoptionally substituted with halogen, methyl, ethyl, —CN, —CF₃, —OH,—OMe, —NH₂, —NO₂, —S(O)₂NH₂, —S(O)₂NHCH₃, —S(O)₂NHCH₂CH₃,—S(O)₂NHCH(CH₃)₂, —S(O)₂N(CH₃)₂, or —S(O)₂NHC(CH₃)₃. In someembodiments, an aryl is optionally substituted with halogen, methyl,ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments, the aryl isoptionally substituted with halogen. In some embodiments, the aryl issubstituted with alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl,wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl isindependently unsubstituted, or substituted with halogen, methyl, ethyl,—CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e., skeletalatoms) is a carbon atom. In some embodiments, cycloalkyls are saturatedor partially unsaturated. In some embodiments, cycloalkyls arespirocyclic or bridged compounds. In some embodiments, cycloalkyls arefused with an aromatic ring (in which case the cycloalkyl is bondedthrough a non-aromatic ring carbon atom). Cycloalkyl groups includegroups having from 3 to 10 ring atoms. Representative cycloalkylsinclude, but are not limited to, cycloalkyls having from three to tencarbon atoms, from three to eight carbon atoms, from three to six carbonatoms, or from three to five carbon atoms. Monocyclic cycloalkylradicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, themonocyclic cycloalkyl is cyclopentyl. In some embodiments, themonocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In someembodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclicradicals include, for example, adamantyl, 1,2-dihydronaphthalenyl,1,4-dihydronaphthalenyl, tetrainyl, decalinyl,3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl andbicycle[1.1.1]pentyl. Unless otherwise stated specifically in thespecification, a cycloalkyl group may be optionally substituted.Representative cycloalkyls include, but are not limited to, cycloalkylshaving from three to fifteen carbon atoms (C₃-C₁₅ cycloalkyl), fromthree to ten carbon atoms (C₃-C₁₀ cycloalkyl), from three to eightcarbon atoms (C₃-C₈ cycloalkyl), from three to six carbon atoms (C₃-C₆cycloalkyl), from three to five carbon atoms (C₃-C₅ cycloalkyl), orthree to four carbon atoms (C₃-C₄ cycloalkyl). A cycloalkyl can comprisea fused, spiro or bridged ring system. In some embodiments, thecycloalkyl comprises a fused ring system. In some embodiments, thecycloalkyl comprises a spiro ring system. In some embodiments, thecycloalkyl comprises a bridged ring system. In some embodiments, thecycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, thecycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkylsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocyclesinclude, for example, adamantyl, norbornyl, decalinyl,bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin,bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkylsinclude, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Unless stated otherwise specifically in the specification,a cycloalkyl is optionally substituted, for example, with oxo, halogen,amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl,alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Insome embodiments, a cycloalkyl is optionally substituted with oxo,halogen, methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, a cycloalkyl is optionally substituted with oxo, halogen,methyl, ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments, thecycloalkyl is optionally substituted with halogen.

Heteroalkyl” refers to an alkyl group in which one or more skeletalatoms of the alkyl are selected from an atom other than carbon, e.g.,oxygen, nitrogen (e.g., —NH—, —N(alkyl)-), sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C₁-C₆heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atomsand one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.—NH—, —N(alkyl)-), sulfur, or combinations thereof wherein theheteroalkyl is attached to the rest of the molecule at a carbon atom ofthe heteroalkyl. Examples of such heteroalkyl are, for example,—CH₂—O—CH₂—, —CH₂—N(alkyl)-CH₂—, —CH₂—N(aryl)-CH₂—, —OCH₂CH₂O—,—OCH₂CH₂OCH₂CH₂O—, or —OCH₂CH₂OCH₂CH₂OCH₂CH₂O—. Unless stated otherwisespecifically in the specification, a heteroalkyl is optionallysubstituted for example, with oxo, halogen, amino, nitrile, nitro,hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, aheteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl,—CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, a heteroalkylis optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF₃,—OH, or —OMe. In some embodiments, the heteroalkyl is optionallysubstituted with halogen.

The term “heterocycloalkyl” refers to a cycloalkyl group that includesat least one heteroatom selected from nitrogen, oxygen, and sulfur.Unless stated otherwise specifically in the specification, theheterocycloalkyl radical may be a monocyclic, or bicyclic ring system,which may include fused (when fused with an aryl or a heteroaryl ring,the heterocycloalkyl is bonded through a non-aromatic ring atom) orbridged ring systems. The nitrogen, carbon or sulfur atoms in theheterocyclyl radical may be optionally oxidized. The nitrogen atom maybe optionally quaternized. The heterocycloalkyl radical is partially orfully saturated. Examples of heterocycloalkyl radicals include, but arenot limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl,tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes allring forms of carbohydrates, including but not limited tomonosaccharides, disaccharides and oligosaccharides. Unless otherwisenoted, heterocycloalkyls have from 2 to 12 carbons in the ring. In someembodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. Insome embodiments, heterocycloalkyls have from 2 to 10 carbons in thering and 1 or 2 N atoms. In some embodiments, heterocycloalkyls havefrom 2 to 10 carbons in the ring and 3 or 4 N atoms. In someembodiments, heterocycloalkyls have from 2 to 12 carbons, 0-2 N atoms,0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In someembodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms,0-1 O atoms, and 0-1 S atoms in the ring. It is understood that whenreferring to the number of carbon atoms in a heterocycloalkyl, thenumber of carbon atoms in the heterocycloalkyl is not the same as thetotal number of atoms (including the heteroatoms) that make up theheterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring).Unless stated otherwise specifically in the specification, aheterocycloalkyl is optionally substituted, for example, with oxo,halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl,haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, andthe like. In some embodiments, a heterocycloalkyl is optionallysubstituted with oxo, halogen, methyl, ethyl, —CN, —CF₃, —OH, —OMe,—NH₂, or —NO₂. In some embodiments, a heterocycloalkyl is optionallysubstituted with oxo, halogen, methyl, ethyl, —CN, —CF₃, —OH, or —OMe.In some embodiments, the heterocycloalkyl is optionally substituted withhalogen.

“Heteroaryl” refers to a ring system radical comprising carbon atom(s)and one or more ring heteroatoms that selected from the group consistingof nitrogen, oxygen, phosphorous, and sulfur, and at least one aromaticring. In some embodiments, heteroaryl is monocyclic, bicyclic orpolycyclic. Illustrative examples of monocyclic heteroaryls includepyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene,indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline,cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, andpteridine. Illustrative examples of monocyclic heteroaryls includepyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, and furazanyl. Illustrative examples of bicyclicheteroaryls include indolizine, indole, benzofuran, benzothiophene,indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline,cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, andpteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl,pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In someembodiments, a heteroaryl contains 0-6 N atoms in the ring. In someembodiments, a heteroaryl contains 1-4 N atoms in the ring. In someembodiments, a heteroaryl contains 4-6 N atoms in the ring. In someembodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, 0-1 Patoms, and 0-1 S atoms in the ring. In some embodiments, a heteroarylcontains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In someembodiments, heteroaryl is a C₁-C₉ heteroaryl. In some embodiments,monocyclic heteroaryl is a C₁-C₅ heteroaryl. In some embodiments,monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In someembodiments, a bicyclic heteroaryl is a C₆-C₉ heteroaryl. In someembodiments, a heteroaryl group comprises a partially reduced cycloalkylor heterocycloalkyl group defined herein (e.g., 7,8-dihydroquinoline).In some embodiments, a heteroaryl group comprises a fully reducedcycloalkyl or heterocycloalkyl group defined herein (e.g.,5,6,7,8-tetrahydroquinoline). When heteroaryl comprises a cycloalkyl orheterocycloalkyl group, the heteroaryl is bonded to the rest of themolecule through a heteroaromatic ring carbon or hetero atom. Aheteroaryl radical can be a monocyclic or polycyclic (e.g., bicyclic,tricyclic, or tetracyclic) ring system, which may include fused, spiroor bridged ring systems. Unless stated otherwise specifically in thespecification, a heteroaryl is optionally substituted, for example, withhalogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl,haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, andthe like. In some embodiments, a heteroaryl is optionally substitutedwith halogen, methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH2, or —NO₂. Insome embodiments, a heteroaryl is optionally substituted with halogen,methyl, ethyl, —CN, —CF3, —OH, or —OMe. In some embodiments, theheteroaryl is optionally substituted with halogen.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well aswords stemming therefrom, as used herein, do not necessarily imply 100%or complete treatment, prevention, amelioration, or inhibition. Rather,there are varying degrees of treatment, prevention, amelioration, andinhibition of which one of ordinary skill in the art recognizes ashaving a potential benefit or therapeutic effect. In this respect, thedisclosed methods can provide any amount of any level of treatment,prevention, amelioration, or inhibition of the disorder in a mammal. Forexample, a disorder, including symptoms or conditions thereof, may bereduced by, for example, about 100%, about 90%, about 80%, about 70%,about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.Furthermore, the treatment, prevention, amelioration, or inhibitionprovided by the methods disclosed herein can include treatment,prevention, amelioration, or inhibition of one or more conditions orsymptoms of the disorder, e.g., cancer or an inflammatory disease. Also,for purposes herein, “treatment,” “prevention,” “amelioration,” or“inhibition” encompass delaying the onset of the disorder, or a symptomor condition thereof. As used herein, “treating” includes the conceptsof “alleviating”, which refers to lessening the frequency of occurrenceor recurrence, or the severity, of any symptoms or other ill effectsrelated to a disorder and/or the associated side effects. The term“treating” also encompasses the concept of “managing” which refers toreducing the severity of a particular disease or disorder in a patientor delaying its recurrence, e.g., lengthening the period of remission ina patient who had suffered from the disease. The term “treating” furtherencompasses the concept of “prevent,” “preventing,” and “prevention,”that is, reducing the probability of developing a disease or conditionin a subject, who does not have, but is at risk of or susceptible todeveloping a disease or condition.

The term “therapeutically effective amount” as used herein to refer toan amount effective at the dosage and duration necessary to achieve thedesired therapeutic result. A therapeutically effective amount of thecomposition may vary depending on factors such as the individual'scondition, age, sex, and weight, and the ability of the protein toelicit the desired response of the individual. A therapeuticallyeffective amount can also be an amount that exceeds any toxic ordeleterious effect of the composition that would have a beneficialeffect on the treatment.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl” as defined above.Further, an optionally substituted group may be un-substituted (e.g.,—CH₂CH₃), fully substituted (e.g., —CF₂CF₃), mono-substituted (e.g.,—CH₂CH₂F) or substituted at a level anywhere in-between fullysubstituted and mono-substituted (e.g., —CH₂CHF₂, —CH₂CF₃, —CF₂CH₃,—CFHCHF₂, etc.).

As used herein, the term “substituent” means positional variables on theatoms of a core molecule that are substituted at a designated atomposition, replacing one or more hydrogens on the designated atom,provided that the designated atom's normal valency is not exceeded, andthat the substitution results in a stable compound. Combinations ofsubstituents and/or variables are permissible only if such combinationsresult in stable compounds. A person of ordinary skill in the art shouldnote that any carbon as well as heteroatom with valences that appear tobe unsatisfied as described or shown herein is assumed to have asufficient number of hydrogen atom(s) to satisfy the valences describedor shown. In certain instances one or more substituents having a doublebond (e.g., “oxo” or “═O”) as the point of attachment may be described,shown or listed herein within a substituent group, wherein the structuremay only show a single bond as the point of attachment to the corestructure. A person of ordinary skill in the art would understand that,while only a single bond is shown, a double bond is intended for thosesubstituents.

The term “optionally substituted” or “substituted” means that thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from D, halogen, —CN,oxo, —NH₂, —NH(alkyl), —N(alkyl)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some embodiments, optional substituents are independently selectedfrom D, halogen, —CN, oxo, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H,—CO₂(C₁-C₄alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂,—S(—O)₂NH₂, —S(—O)₂NH(C₁-C₄alkyl), —S(—O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl,C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl, and—S(═O)₂C₁-C₄alkyl. In some embodiments, optional substituents areindependently selected from D, halogen, —CN, —NH₂, —OH, —NH(CH₃),—N(CH₃)₂, —NH(cyclopropyl), —CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. Insome embodiments, substituted groups are substituted with one or two ofthe preceding groups. When indicating the number of substituents, theterm “one or more” means from one substituent to the highest possiblenumber of substitutions, i.e. replacement of one hydrogen up toreplacement of all hydrogens by substituents.

The term “unsubstituted” means that the specified group bears nosubstituents.

Certain compounds described herein may exist in tautomeric forms, andall such tautomeric forms of the compounds being within the scope of thedisclosure.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of thedisclosure.

The term “peptide” as used herein refers to a compound that includes twoor more amino acids. A peptide described herein can comprise one or moreunnatural amino acids. The term “peptide” also encompasses peptidemimetics. In the present disclosure, the term “amino acid” is used inits broadest meaning and it embraces not only natural amino acids butalso derivatives thereof and artificial amino acids. For example, theterm “amino acid” encompasses unnatural amino acids.

As used herein, the term “unnatural amino acid” refers to an amino acidother than the 20 amino acids that occur naturally in protein.

The term “protein” as used herein refers to a polypeptide (i.e., astring of at least 3 amino acids linked to one another by peptidebonds). Proteins can include moieties other than amino acids (e.g., maybe glycoproteins, proteoglycans, etc.) and/or can be otherwise processedor modified. A protein can be a complete polypeptide as produced byand/or active in a cell (with or without a signal sequence). In someembodiments, a protein is or comprises a characteristic portion such asa polypeptide as produced by and/or active in a cell. A protein caninclude more than one polypeptide chain.

The term “peptide mimetic” or “mimetic” refers to biologically activecompounds that mimic the biological activity of a peptide or a proteinbut are no longer entirely peptidic in chemical nature, e.g., they cancontain non-peptide bonds (that are, bonds other than amide bondsbetween amino acids). As used herein, the term peptide mimetic is usedin a broader sense to include molecules that are no longer completelypeptidic in nature, such as pseudo-peptides, semi-peptides and peptoids.Whether completely or partially non-peptide, peptide mimetics describedherein can provide a spatial arrangement of reactive chemical moietiesthat closely resemble the three-dimensional arrangement of active groupsin the subject amino acid sequence or subject molecule on which thepeptide mimetic is based. As a result of this similar active-sitegeometry, the peptide mimetic can have effects on biological systemsthat are similar to the biological activity of the subject entity.

In some embodiments, the peptide mimetics are substantially similar inboth three-dimensional shape and biological activity to the subjectamino acid sequence or subject molecule on which the peptide mimetic isbased. Examples of methods of structurally modifying a peptide to createa peptide mimetic include the inversion of backbone chiral centersleading to D-amino acid residue structures that may, particularly at theN-terminus, lead to enhanced stability for proteolytical degradationwithout adversely affecting activity. An example is described in thepaper “Tritiated D-alai-Peptide T Binding”, Smith C. S. et al., DrugDevelopment Res., 15, pp. 371-379 (1988). A second method is alteringcyclic structure for stability, such as N to C interchain imides andlactames (Ede et al. in Smith and Rivier (Eds.) “Peptides: Chemistry andBiology”, Escom, Leiden (1991), pp. 268-270). An example of this isprovided in conformationally restricted thymopentin-like compounds, suchas those disclosed in U.S. Pat. No. 4,457,489. A third method is tosubstitute peptide bonds in the subject entity by pseudopeptide bondsthat confer resistance to proteolysis.

Ranges provided herein are understood to be shorthand for all of thevalues within the range. For example, a range of 1 to 50 is understoodto include any number, combination of numbers, or sub-range from thegroup consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50,as well as all intervening decimal values between the aforementionedintegers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8,and 1.9. With respect to sub-ranges, “nested sub-ranges” that extendfrom either end point of the range are specifically contemplated. Forexample, a nested sub-range of an exemplary range of 1 to 50 maycomprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

As used herein, C₁-C_(X) (or C_(1-X)) includes C₁-C₂, C₁-C₃ . . .C₁-C_(X). By way of example only, a group designated as “C₁-C₄”indicates that there are one to four carbon atoms in the moiety, i.e.,groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4carbon atoms. Thus, by way of example only, “C₁-C₄ alkyl” indicates thatthere are one to four carbon atoms in the alkyl group, i.e., the alkylgroup is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, and t-butyl. Also, by way of example, C₀-C₂alkylene includes a direct bond, —CH₂—, and —CH₂CH₂— linkages.

The term “cyclized” or “cyclization” as used herein means that two aminoacids apart from each other by at least one amino acid bind directly orbind indirectly to each other in one peptide to form a cyclic structurein the molecule. In some cases, the two amino adds bind via a linker orthe like.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a companion animal such as a dog or acat. In one aspect, the mammal is a human.

The term “therapeutically effective amount” as used herein to refer toan amount effective at the dosage to achieve the desired therapeuticresult. A therapeutically effective amount of a composition may varydepending on factors such as the individual's condition (e.g., age, sex,and weight), the radiopharmaceutical conjugate, and the method ofadministration (e.g., oral or parenteral).

II. Technical Overview

Targeted Radiopharmaceutical (TRP) is a new generation of nuclearmedicine for cancer treatment or diagnosis. A TRP can selectivelydeliver high concentration of radionuclide-containing molecules to thetarget cells such as tumor, and none or very low concentration to theundesired cells like normal tissues. The process can be achieved byengineering the drug molecule with the high-affinity binder (e.g.,targeting ligands) linking to the radioactive isotope. The biologicaltargets of those binders are highly expressed on tumor cells, have lowor no expression in healthy tissues and organs. When the radioisotopedecays, it emits highly energic ionizing radiation in form of alpha,beta, and/or gamma particles. The released energy at the target sitescan cause damage or death of the target tissues or be visualized byimaging scanner to achieve therapeutic or diagnostic purposes.

In some traditional radiopharmaceutical formulations, a very highconcentration of stabilizer as to radiopharmaceuticals is used. The highconcentration can produce unknown biological effects and/or compromisetherapeutic efficacy of the drug. Due to the low efficiency of thosestabilizers used in the past, significant dilution was needed to slowdown the decomposition. As a result, larger volume of dose can requiretreatment via infusion instead of bolus injection under clinicalsetting. This is less desired for patients due to the prolonged stay atthe infusion center and sometimes hospitalization. One of the majorchallenges in the production of radiopharmaceutical drugs is to extendthe shelf-life of product to allow treatment of patients at remotelocations to the manufacturer site. Increasing stability ofradiopharmaceutical drug in formulated solution can resolve thischallenge.

In some cases, with decay of the parent isotopes, daughter isotopes canbe released into the solution. They can be non-radioactive orradioactive. When the daughter ions are radioactive, those non-bondedions can create non-specific distribution of radioactivity in vivo andgenerate undesired toxicities. In addition, even if they are notradioactive, they can still bind to the metal chelation moiety on theradiopharmaceutical drug due to their higher affinity. The replacementof their parent ions can chemically cause decomposition of the drugsubstance. This process can also negatively impact the radiochemicalpurities overtime. When decay of Actinium-225-DOTA-containing drugstarts, the isotope can first decay into Francium-221(I). The recoilenergy of the process can be approximately 10000 times higher than anyknown chemical bond energy. It can cause the daughter ions to escapefrom their original chelator DOTA. Due to the chemical nature ofFrancium-221 (I), in some cases, they cannot be recaptured by freeDOTA-containing drug. As decay continues, more free daughter ions canenter the solution. Eventually, majority of the decayed daughters canaccumulate in the form of stable Bismuth-209 (III). Bismuth (III) can bea much stronger metal to be chelated with DOTA moiety and itscompetition with the parent drug can lead further dissociation of Ac-225for its chelator, generate radioactive free metal impurities.

The decay of radionuclides can be accompanied by emission of energy inthe form of alpha, beta and/or gamma radiations. The energy can go intothe drug-containing solution and can break chemical bonds, generatereactive chemical species from solvent molecules, further decompose theradiopharmaceutical drug directly or indirectly. This process can bereferred as radiolysis. Radiolysis can be particularly severer when aconcentrated radioactive compound is presented in small volume of thesolution. In the case of Actinium-225-DOTA-containingradiopharmaceuticals, Actinium-225 can decay into Francium-221,Astatine-217, Bismuth-213, Thallium-209, Polonium-213, Lead-209,Bismuth-209 in sequence. The decay chain can contain four alpha particleemissions and two beta particle emissions. In addition, Francium-221 andBismuth-213 can release up to 25% of their decay energy through gammaemission. The ionizing radiation can cause radiolysis of surroundingwater molecules particularly produce H. atoms, .OH radicals, H₃O⁺ ionsand oxidizing agent hydrogen peroxide. These chemical species can behighly reactive. In some cases. they can react with the drug substance,cause degradation of the radioisotope-containing peptide drug, increaseradioactive impurity overtime.

Accordingly, provided herein are radiopharmaceutical compositions withimproved stability, for example, compositions containing Actinium-225.

In one aspect, the present disclosure relates to radionuclide solutionwith radioisotopes and its daughter ions. The solution composition cancomprise ingredients which stabilize the radioactive drug substance fromradiolysis and chemical decomposition. The increased stability of thedrug substance can extend shelf-life of radiopharmaceuticals, as such toachieve their wide applications as a drug product for their diagnosticand therapeutic purpose.

In one aspect, the compositions described herein have increasedstability of the radiopharmaceutical conjugate. The radiopharmaceuticalcomposition can contain ingredients, such as radiopharmaceuticalstabilizers, which stabilize the radioactive drug substance fromradiolysis and chemical decomposition. The radiopharmaceuticalsstabilizers can comprise reducing agents and/or radical scavengers, suchas ascorbic acid to reduce the radiolysis. The composition of thepresent disclosure can have extended shelf-life. The compositionsdescribed herein can comprise one or more stabilizing agents. Thestabilizing agents can prevent or delay radiolysis of theradiopharmaceutical conjugate. The stabilizing agents can prevent ordelay decomposition of the radiopharmaceutical conjugate. Thestabilizing agents can prevent or delay chemical decomposition of theradiopharmaceutical conjugate caused by radioactive decay-generateddaughter ions. The stabilizing agents can prevent or delay chemicaldecomposition of the radiopharmaceutical conjugate caused by pH changes.The stabilizing agents can be added into the composition at a lowconcentration. The stabilizing agents can be optionally added into thecomposition at a low concentration. The increased stability of theradiopharmaceutical conjugate can achieve one or more applications. Theapplications can comprise acting as a drug product for one or morediagnostic purposes. The applications can comprise acting as a drugproduct for one or more therapeutic purposes. A treatment plan for apatient or subject receiving the radiopharmaceutical compositionsdescribed herein can include treatment at remote locations. A treatmentplan for a patient or subject receiving the radiopharmaceuticalcompositions described herein can include a shorter stay at the infusioncenter or at the hospital.

A radiopharmaceutical conjugate can comprise a radionuclide and a metalchelator. The radionuclide and the metal chelator can be linked by ionicand coordinate bonding. The radionuclides for therapeutic purpose caninclude Lutetium-177, Actinium-225, Yttrium-90, and Bismuth-213. Theradionuclides for diagnostic purpose can include Gallium-68, Copper-64,and Indium-111. The chelator can further bind to a target binder, suchas one that has a high-affinity with the target of theradiopharmaceutical conjugate, directly or via a linker covalently.Exemplary metal chelators can include aza-crown ether-basedpolycarboxylic acid such as2,2′,2″,2′″-(1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrayl)tetraaceticacid (DOTA), or 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA). Thechelation can keep the radionuclide from releasing into surroundings invitro and/or in vivo.

III. Compositions

In one aspect, the present disclosure provides liquidradiopharmaceutical compositions comprising a radiopharmaceuticalconjugate. The conjugate can comprise a targeting ligand. The targetingligand can be a binding peptide or a chemical group. The conjugate canfurther comprise a chelator such as a metal chelator. The chelator canbe covalently attached to the targeting ligand. The conjugate canfurther comprise a radionuclide. In some embodiments, the radionuclideis bound to the chelator. The composition can further comprise one ormore stabilizing agents. The one or more stabilizing agents are agentsthat can stabilize the composition or formulation of theradiopharmaceutical conjugates. The one or more stabilizing agents canreduce or delay the decomposition of the radiopharmaceutical conjugatesin the composition.

In one aspect, provided herein are liquid radiopharmaceuticalcompositions comprising ²²⁵Ac-DOTATATE. In one aspect, provided hereinare liquid radiopharmaceutical compositions comprising ²²⁵Ac-DOTATOC.

The liquid radiopharmaceutical compositions can comprisepharmaceutically acceptable carriers or diluents. Exemplarypharmaceutically acceptable carriers include solvents (aqueous ornon-aqueous), solutions, emulsions, dispersion media, coatings, isotonicand absorption promoting or delaying agents, compatible withpharmaceutical administration. In some embodiments, the liquidradiopharmaceutical compositions described herein are formulated as asolution, emulsion, suspension, syrup or elixir, or the like. Thecompositions can be aqueous radiopharmaceutical compositions.

The liquid radiopharmaceutical composition can comprise an aqueousvehicle. For example, the aqueous vehicle can comprise water, salinesolution, dextrose in water, dextrose in saline solution, Ringer'ssolution, or lactated Ringer's solution. In some embodiments, theaqueous vehicle is water. In some embodiments, the aqueous vehicle iswater for injection. In some embodiments, the aqueous vehicle is 5.0%w/w sodium chloride solution. In some embodiments, the aqueous vehicleis 4.0% w/w sodium chloride solution. In some embodiments, the aqueousvehicle is 3.0% sodium chloride solution. In some embodiments, theaqueous vehicle is 2.0% w/w sodium chloride solution. In someembodiments, the aqueous vehicle is 1.5% w/w sodium chloride solution.In some embodiments, the aqueous vehicle is 1.0% sodium chloridesolution. In some embodiments, the aqueous vehicle is 0.9% w/w sodiumchloride saline solution. In some embodiments, the aqueous vehicle is0.5% w/w sodium chloride solution. In some embodiments, the aqueousvehicle is 0.5% to 1.5% w/w sodium chloride solution. In someembodiments, the aqueous vehicle is 0.7% to 1.1% w/w sodium chloridesolution. In some embodiments, the aqueous vehicle is saline solution.In some embodiments, the aqueous vehicle is dextrose in water. In someembodiments, the aqueous vehicle is dextrose in saline solution. Thecompositions can be isotonic. The compositions can be a solution orsuspension. In some embodiments, the liquid radiopharmaceutical isformulated as a solution. The compositions can be formulated to becompatible with a particular local or systemic route of administration.The compositions can include carriers, diluents, or excipients suitablefor administration by particular routes. The composition can beformulated for IV infusion or bolus injection. In some embodiments, theliquid radiopharmaceutical is formulated for intravenous administration.

Supplementary components or excipients can also be incorporated into theliquid radiopharmaceutical compositions. The composition can furthercomprise one or more supplementary components or excipients. Thesupplementary components or excipients can be preservatives,antibacterial, antiviral, antimicrobial and antifungal agents. Thesupplementary components or excipients can be a tonicity adjustingagent, a solubilizing agent, a suspending agent, and a surfactant.

The liquid radiopharmaceutical compositions described herein can bestorage stable for a period of time. In some embodiments, the liquidradiopharmaceutical compositions described herein retain at least 80 mol% of the initial conjugate after 168 hours at room temperature (25° C.).In some embodiments, the compositions retain at least 85 mol % of theinitial conjugate after 168 hours at room temperature (25° C.). In someembodiments, the compositions retain at least 90 mol % of the initialconjugate after 168 hours at room temperature (25° C.). In someembodiments, the compositions retain at least 95 mol % of the initialconjugate after 168 hours at room temperature (25° C.). In someembodiments, the compositions described retain at least 98 mol % of theinitial conjugate after 168 hours at room temperature (25° C.). In someembodiments, the composition retains at least 85 mol %, at least 90 mol%, at least 92 mol %, at least 95 mol %, at least 98 mol % or at least99 mol % of the initial conjugate after 120 hours at room temperature(25° C.). In some embodiments, the composition retains at least 85 mol%, at least 90 mol %, at least 92 mol %, at least 95 mol %, at least 98mol % or at least 99 mol % of the initial conjugate after 96 hours atroom temperature (25° C.). In some embodiments, the composition retainsat least 85 mol %, at least 90 mol %, at least 92 mol %, at least 95 mol%, at least 98 mol % or at least 99 mol % of the initial conjugate after48 hours at room temperature (25° C.). In some embodiments, thecompositions described herein retain at least 85 mol %, at least 90 mol%, at least 92 mol %, at least 95 mol %, at least 98 mol % or at least99 mol % of the initial conjugate after 2 weeks at refrigeratedcondition (about 4° C.). In some embodiments, the compositions describedherein retain at least 85 mol %, at least 90 mol %, at least 92 mol %,at least 95 mol %, at least 98 mol % or at least 99 mol % of the initialconjugate after 10 days at refrigerated condition (about 4° C.). In someembodiments, the compositions described herein retain at least 85 mol %,least 90 mol %, at least 92 mol %, at least 95 mol %, at least 98 mol %,at least 99 mol %, or at least 99.5 mol % of the initial conjugate after168 hours at refrigerated condition (about 4° C.). In some embodiments,the compositions described herein retain at least 85 mol %, at least 90mol %, at least 92 mol %, at least 95 mol %, at least 98 mol %, at least99 mol %, or at least 99.5 mol % of the initial conjugate after 96 hoursat refrigerated condition (about 4° C.). In some embodiments, thecompositions described herein retain at least 85 mol %, at least 90 mol%, at least 92 mol %, at least 95 mol %, at least 98 mol %, at least 99mol %, or at least 99.5 mol % of the initial conjugate after 48 hours atrefrigerated condition (about 4° C.). In some embodiments, the purity orthe molar percentage of the conjugate is determined by radio thin layerchromatography (radio-TLC). In some embodiments, the purity or the molarpercentage of the conjugate is determined by instant thin layerchromatography (iTLC). In some embodiments, the purity or the molarpercentage of the conjugate is determined by measuring the relatedα-particle emission using radio-TLC.

The liquid radiopharmaceutical compositions described herein can retainan amount of the initial conjugate (such as ²²⁵Ac-DOTA-TATE) afterstored for a period of time. In some embodiments, theradiopharmaceutical composition retains 95 mol % or more of the initialconjugate after 48 hours, 72 hours, 96 hours, 120 hours, 148 hours, 168hours, 192 hours, or 216 hours at room temperature (25° C.). In someembodiments, the radiopharmaceutical composition retains 95 mol % ormore of the initial conjugate after 96 hours at room temperature (25°C.). In some embodiments, the radiopharmaceutical composition retains 95mol % or more of the initial conjugate after 120 hours at roomtemperature (25° C.). In some embodiments, the radiopharmaceuticalcomposition retains 95 mol % or more of the initial conjugate after 148hours at room temperature (25° C.). In some embodiments, theradiopharmaceutical composition retains 95 mol % or more of the initialconjugate after 168 hours at room temperature (25° C.). In someembodiments, the radiopharmaceutical composition retains 95 mol % ormore of the initial conjugate after 192 hours at room temperature (25°C.). In some embodiments, the purity or the molar percentage of theconjugate is determined by instant thin-layer chromatography (iTLC). Insome embodiments, the purity or the molar percentage of the conjugate isdetermined by radio thin-layer chromatography (radio-TLC).

The liquid radiopharmaceutical compositions described herein can containa small amount of the unchelated and un-conjugated radionuclide afterstored for a period of time. In some embodiments, the liquidradiopharmaceutical compositions described herein contain a small amountof free actinium-225 and actinium-225 present in a fragment of theconjugate ²²⁵Ac-DOTA-TATE (e.g., as ²²⁵Ac-DOTA fragment) after beingstored for a period of time. For example, see Example 3. A total contentof the radionuclide such as actinium-225 in the radiopharmaceuticalcomposition can also decrease over time due to the decay of theradionuclide. In some embodiments, the liquid radiopharmaceuticalcompositions comprise a conjugate that comprises actinium-225. In someembodiments, a radiopharmaceutical composition comprising actinium-225conjugates contains no more than about 20% free actinium-225 after 120hours at about 20° C. to 25° C., compared to the total amount of theactinium-225 content in the composition (at that time). In someembodiments, a radiopharmaceutical composition comprising actinium-225conjugates contains no more than about 10% free actinium-225 after 120hours at about 20° C. to 25° C., compared to the total amount of theactinium-225 content in the composition. In some embodiments, aradiopharmaceutical composition comprising actinium-225 conjugatescontains no more than about 5% free actinium-225 after 120 hours atabout 20° C. to 25° C., compared to the total amount of the actinium-225content in the composition. In some embodiments, a radiopharmaceuticalcomposition comprising actinium-225 conjugates contains no more thanabout 2% free actinium-225 after 120 hours at about 20° C. to 25° C.,compared to the total amount of the actinium-225 content in thecomposition. In some embodiments, a radiopharmaceutical compositioncomprising actinium-225 conjugates contains no more than about 1% freeactinium-225 after 120 hours at about 20° C. to 25° C., compared to thetotal amount of the actinium-225 content in the composition.

In some embodiments, after being stored for 120 hours at about 20° C. toabout 25° C., at least 90 mol % of the ²²⁵Ac (i.e., actinium-225)content in the liquid radiopharmaceutical composition (at that time) ispresent as ²²⁵Ac-DOTA-TATE. In some embodiments, after being stored for120 hours at about 20° C. to about 25° C., at least 95 mol % of the²²⁵Ac (i.e., actinium-225) content in the liquid radiopharmaceuticalcomposition is present as ²²⁵Ac-DOTA-TATE. In some embodiments, afterbeing stored for 120 hours at about 20° C. to about 25° C., at least 98mol % of the ²²⁵Ac (i.e., actinium-225) content in the liquidradiopharmaceutical composition is present as ²²⁵Ac-DOTA-TATE. In someembodiments, after being stored for 120 hours at about 20° C. to about25° C., at least 99 mol % of the ²²⁵Ac (i.e., actinium-225) content inthe liquid radiopharmaceutical composition is present as²²⁵Ac-DOTA-TATE. In some embodiments, after being stored for 144 hoursat about 20° C. to about 25° C., at least 90 mol % of the ²²⁵Ac (i.e.,actinium-225) content in the liquid radiopharmaceutical composition (atthat time) is present as ²²⁵Ac-DOTA-TATE. In some embodiments, afterbeing stored for 168 hours at about 20° C. to about 25° C., at least 90mol % of the ²²⁵Ac (i.e., actinium-225) content in the liquidradiopharmaceutical composition (at that time) is present as²²⁵Ac-DOTA-TATE. In some embodiments, after being stored for 192 hoursat about 20° C. to about 25° C., at least 90 mol % of the ²²⁵Ac (i.e.,actinium-225) content in the liquid radiopharmaceutical composition (atthat time) is present as ²²⁵Ac-DOTA-TATE.

In some embodiments, a radiopharmaceutical composition comprisingactinium-225 conjugates contains no more than a combined amount of about20% of free ²²⁵Ac and ²²⁵Ac present in a fragment of the conjugate(e.g., as ²²⁵Ac-DOTA fragment) after 120 hours at about 20° C. to 25°C., compared to the total amount of the ²²⁵Ac content in thecomposition. In some embodiments, a radiopharmaceutical compositioncomprising actinium-225 conjugates contains no more than a combinedamount of about 15% of free ²²⁵Ac and ²²⁵Ac present in a fragment of theconjugate (e.g., as ²²⁵Ac-DOTA fragment) after 120 hours at about 20° C.to 25° C., compared to the total amount of the ²²⁵Ac content in thecomposition. In some embodiments, a radiopharmaceutical compositioncomprising actinium-225 conjugates contains no more than a combinedamount of about 10% of free ²²⁵Ac and ²²⁵Ac present in a fragment of theconjugate (e.g., as ²²⁵Ac-DOTA fragment) after 120 hours at about 20° C.to 25° C., compared to the total amount of the ²²⁵Ac content in thecomposition. In some embodiments, a radiopharmaceutical compositioncomprising actinium-225 conjugates contains no more than a combinedamount of about 10% of free ²²⁵Ac and ²²⁵Ac present in a fragment of theconjugate (e.g., as ²²⁵Ac-DOTA fragment) after 120 hours at about 20° C.to 25° C., compared to the total amount of the ²²⁵Ac content in thecomposition. In some embodiments, a radiopharmaceutical compositioncomprising actinium-225 conjugates contains no more than a combinedamount of about 5% of free ²²⁵Ac and ²²⁵Ac present in a fragment of theconjugate (e.g., as ²²⁵Ac-DOTA fragment) after 120 hours at about 20° C.to 25° C., compared to the total amount of the ²²⁵Ac content in thecomposition. The total amount of the ²²⁵Ac content in a composition candecrease overtime as the radionuclide actinium-225 naturally decays. Insome embodiments, a radiopharmaceutical composition comprisingactinium-225 conjugates contains no more than a combined amount of about10% of free ²²⁵Ac and ²²⁵Ac present in a fragment of the conjugate(e.g., as ²²⁵Ac-DOTA fragment) after 144 hours at about 20° C. to 25°C., compared to the total amount of the ²²⁵Ac content in thecomposition. In some embodiments, a radiopharmaceutical compositioncomprising actinium-225 conjugates contains no more than a combinedamount of about 10% of free ²²⁵Ac and ²²⁵Ac present in a fragment of theconjugate (e.g., as ²²⁵Ac-DOTA fragment) after 168 hours at about 20° C.to 25° C., compared to the total amount of the ²²⁵Ac content in thecomposition. In some embodiments, a radiopharmaceutical compositioncomprising actinium-225 conjugates contains no more than a combinedamount of about 10% of free ²²⁵Ac and²²⁵Ac present in a fragment of theconjugate (e.g., as ²²⁵Ac-DOTA fragment) after 192 hours at about 20° C.to 25° C., compared to the total amount of the ²²⁵Ac content in thecomposition. In some embodiments, the amount of ²²⁵Ac is determined byradio-TLC.

In some embodiments, a radiopharmaceutical composition described hereinretains at least 90% of the ²²⁵Ac (i.e., actinium-225) content in theliquid radiopharmaceutical composition as ²²⁵Ac-DOTA-TATE after 120hours at about 20° C. to 25° C. as determined by radio-TLC. In someembodiments, a radiopharmaceutical composition described herein retainsat least 95% of the ²²⁵Ac (i.e., actinium-225) content in the liquidradiopharmaceutical composition as ²²⁵Ac-DOTA-TATE after 120 hours atabout 20° C. to 25° C. as determined by radio-TLC. In some embodiments,a radiopharmaceutical composition described herein retains at least 98%of the ²²⁵Ac (i.e., actinium-225) content in the liquidradiopharmaceutical composition as ²²⁵Ac-DOTA-TATE after 120 hours atabout 20° C. to 25° C. as determined by radio-TLC. In some embodiments,a radiopharmaceutical composition described herein retains at least 99%of the ²²⁵Ac (i.e., actinium-225) content in the liquidradiopharmaceutical composition as ²²⁵Ac-DOTA-TATE after 120 hours atabout 20° C. to 25° C. as determined by radio-TLC. In some embodiments,a radiopharmaceutical composition described herein retains at least 90%of the ²²⁵Ac (i.e., actinium-225) content in the liquidradiopharmaceutical composition as ²²⁵Ac-DOTA-TATE after 144 hours atabout 20° C. to 25° C. as determined by radio-TLC. In some embodiments,a radiopharmaceutical composition described herein retains at least 90%of the ²²⁵Ac (i.e., actinium-225) content in the liquidradiopharmaceutical composition as ²²⁵Ac-DOTA-TATE after 168 hours atabout 20° C. to 25° C. as determined by radio-TLC. In some embodiments,a radiopharmaceutical composition described herein retains at least 90%of the ²²⁵Ac (i.e., actinium-225) content in the liquidradiopharmaceutical composition as ²²⁵Ac-DOTA-TATE after 192 hours atabout 20° C. to 25° C. as determined by radio-TLC.

In some embodiments, a radiopharmaceutical composition comprisingactinium-225 conjugates contains no more than about 20% free actiniumafter 168 hours at room temperature (25° C.), compared to the totalamount of the initial chelated actinium content in the composition. Insome embodiments, a radiopharmaceutical composition comprisingactinium-225 conjugates contains no more than about 10% free actiniumafter 168 hours at room temperature (25° C.), compared to the totalamount of the initial chelated actinium content in the composition. Insome embodiments, a radiopharmaceutical composition comprisingactinium-225 conjugates contains no more than about 5% free actiniumafter 168 hours at room temperature (25° C.), compared to the totalamount of the initial chelated actinium content in the composition. Insome embodiments, a radiopharmaceutical composition comprisingactinium-225 conjugates contains no more than about 3% free actiniumafter 168 hours at room temperature (25° C.), compared to the totalamount of the initial chelated actinium content in the composition. Insome embodiments, a radiopharmaceutical composition comprisingactinium-225 conjugates contains no more than about 2% free actiniumafter 168 hours at room temperature (25° C.), compared to the totalamount of the initial chelated actinium content in the composition. Insome embodiments, a radiopharmaceutical composition comprisingactinium-225 conjugates contains no more than about 1% free actiniumafter 168 hours at room temperature (25° C.), compared to the totalamount of the initial chelated actinium content in the composition. Insome embodiments, a radiopharmaceutical composition comprisingactinium-225 conjugates contains no more than about a total of 20 mol %of free daughter isotopes of actinium-225 after 168 hours at roomtemperature (25° C.), compared to the total amount of the initialchelated actinium content in the composition. In some embodiments, aradiopharmaceutical composition comprising actinium-225 conjugatescontains no more than about a total of 15 mol % of free daughterisotopes of actinium-225 after 168 hours at room temperature (25° C.),compared to the total amount of the initial chelated actinium content inthe composition. In some embodiments, a radiopharmaceutical compositioncomprising actinium-225 conjugates contains no more than about a totalof 10 mol % of free daughter isotopes of actinium-225 after 168 hours atroom temperature (25° C.), compared to the total amount of the initialchelated actinium content in the composition. In some embodiments, aradiopharmaceutical composition comprising actinium-225 conjugatescontains no more than about a total of 5 mol % of free daughter isotopesof actinium-225 after 168 hours at room temperature (25° C.), comparedto the total amount of the initial chelated actinium content in thecomposition. In some embodiments, a radiopharmaceutical compositioncomprising actinium-225 conjugates contains no more than about a totalof 3 mol % of free daughter isotopes of actinium-225 after 168 hours atroom temperature (25° C.), compared to the total amount of the initialchelated actinium content in the composition. In some embodiments, aradiopharmaceutical composition comprising actinium-225 conjugatescontains no more than about a total of 2 mol % of free daughter isotopesof actinium-225 after 168 hours at room temperature (25° C.), comparedto the total amount of the initial chelated actinium content in thecomposition. In some embodiments, a radiopharmaceutical compositioncomprising actinium-225 conjugates contains no more than about a totalof 1 mol % of free daughter isotopes of actinium-225 after 168 hours atroom temperature (25° C.), compared to the total amount of the initialchelated actinium content in the composition. In some embodiments, thepurity or the molar percentage of the conjugate is determined by radiothin layer chromatography (radio-TLC).

Stabilizing Agents

In one aspect, disclosed herein are radiopharmaceutical compositionswith improved stability. Pharmaceutical compositions described hereincan comprise one or more stabilizing agents. In one aspect, providedherein are solutions that comprise one or more stabilizing agents foruse in a radiopharmaceutical composition. In some embodiments, thesolutions that comprise one or more stabilizing agents are dilutionsolutions. The one or more stabilizing agents can reduce, prevent, ordelay decomposition of the radiopharmaceutical. The decomposition cancomprise radiolysis-caused decomposition of the radiopharmaceuticals.The one or more stabilizing agents can reduce, prevent, or delay thedecay of radionuclides.

Radiolysis Stabilizer

The one or more stabilizing agents of the herein describedpharmaceutical composition can comprise a radiolysis stabilizer. The oneor more stabilizing agents can comprise two or more radiolysisstabilizers. The one or more stabilizing agents can comprise a first anda second radiolysis stabilizer. The radiolysis stabilizer can be anamino acid or a peptide or a derivative thereof, a vitamin or aderivative thereof, a lipid or a derivative thereof, a carbohydrate or aderivative thereof, a volume expander or an antioxidant.

The molar ratio of the first and the second radiolysis stabilizer can befrom 1:100,000 to 100,000, from 1:1,000 to 1,000:1, from 1:100 to 100:1,from 1:20 to 20:1, from 1:10 to 10:1, and from 1:5 to 5:1. The molarratio of the first and the second radiolysis stabilizer can be from 1:5to 5:1. The radiolysis stabilizer can be present in theradiopharmaceutical composition at a concentration of from about 1 μM,10 μM, 0.1 mM, 1 mM, 5 mM, 10 mM, 25 mM, 50 mM, or 75 mM to about 80 mM,100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 250 mM, 500 mM, 1 M, 2 M, 3 M, 4M, 5 M. The radiolysis stabilizer can be present in theradiopharmaceutical composition at a concentration of from about 1 μM to5 M. The radiolysis stabilizer can be present in the radiopharmaceuticalcomposition at a concentration of from about 10 μM to 1 M. Theradiolysis stabilizer can be present in the radiopharmaceuticalcomposition at a concentration of from about 0.1 mM to 500 mM. Theradiolysis stabilizer can be present in the radiopharmaceuticalcomposition at a concentration of from about 10 mM to 500 mM. Theradiolysis stabilizer can be present in the radiopharmaceuticalcomposition at a concentration of from about 20 mM to 100 mM. Theradiolysis stabilizer can be present in the radiopharmaceuticalcomposition at a concentration of from about 25 mM to 75 mM. Theradiolysis stabilizer can be present in the radiopharmaceuticalcomposition at about 0.001 wt % to about 10 wt %. The radiolysisstabilizer can be present in the radiopharmaceutical composition atabout 0.0001 wt % to about 20 wt %, 0.001 wt % to about 10 wt %, 0.01 wt% to about 5 wt %, about 0.05 wt % to about 2 wt %, or about 0.1 wt % toabout 1 wt %. The radiolysis stabilizer can be present in theradiopharmaceutical composition at about 0.01 wt % to about 5 wt %. Theradiolysis stabilizer can be present in the radiopharmaceuticalcomposition at about 1 wt % to about 10 wt %, about 3 wt % to about 7 wt%, about 4 wt % to about 6 wt %, or about 2 wt % to about 15 wt %. Theradiolysis stabilizer can be present in the radiopharmaceuticalcomposition at about 5 wt %. The radiolysis stabilizer can be present inthe radiopharmaceutical composition at about 0.05 wt % to about 2 wt %.The radiolysis stabilizer can be present in the radiopharmaceuticalcomposition at about 0.1 wt % to about 1 wt %. The radiolysis stabilizercan also be present in the radiopharmaceutical composition at aconcentration of from 0.0001 to 5,000 mg/mL. The radiolysis stabilizercan also be present in the radiopharmaceutical composition at aconcentration of from 0.1 to 500 mg/mL. The radiolysis stabilizer canalso be present in the radiopharmaceutical composition at aconcentration of from 0.01 to 50 mg/mL. The radiolysis stabilizer canalso be present in the radiopharmaceutical composition at aconcentration of from 0.1 to 5 mg/mL. The radiolysis stabilizer can alsobe present in the radiopharmaceutical composition at a concentration offrom 0.5 to 2 mg/mL. In some embodiments, the radiolysis stabilizer isdextran (such as Dextran 40).

The radiolysis stabilizers can comprise an amino acid or a derivativethereof. The radiolysis stabilizers can comprise a peptide or aderivative thereof. The amino acid or a derivative thereof can be anatural amino acid or an unnatural amino acid. The amino acid can act toscavenge chemically active ingredients generated by radiolysis. Theamino acid can contain an amino group. The amino acid can compriseoptionally an extra reducing heteroatom, such as L-methionine,L-Cysteine, or L-Lysine. The peptide or a derivative thereof cancomprise two or more amino acids. The peptide can comprise 2 to 50 aminoacids. The peptide can comprise 2 to 30 amino acids. The peptide cancomprise 2 to 15 amino acids. The peptide can comprise 2 to 7 aminoacids. The peptide can comprise 2 to 4 amino acids. The peptide cancomprise 3 amino acids. The amino acid can be an essential amino acid.The amino acid can be a nonessential amino acid. The amino acid can bean aliphatic amino acid. The amino acid can be an aromatic amino acid.The amino acid can be an acidic amino acid. The amino acid can be abasic amino acid. The amino acid can be a hydroxylic amino acid. Theamino acid can be a sulfur-containing amino acid. The amino acid can bean amidic amino acid. The amino acid, its derivative, or peptide can beN-Acetyl-L-cysteine, Glutathione, L-Lysine, Selenol-L-methionine,Glutathione, Albumin, Melatonin, Taurine, Alanine, Arginine, Asparagine,Aspartic acid, Cysteine, Glutamine, Glutamic acid, Glycine, Histidine,Isoleucine, Lysine, Methionine, Phenylalanine, Proline, Serine,Threonine, Tryptophan, Tyrosine, Valine, and/or derivatives thereof. Theamino acid can be a methionine. The amino acid derivative, such asN-Acetyl-L-cysteine, can have higher solubilities. The radiolysisstabilizer, such as Thiourea, L-Glutathione, and Lipoic Acid, cancomprise an organic sulfur. The organic sulfur can optionally beoxidized to a higher oxidation state and coordinate to free heavy metalions in a solution.

The radiolysis stabilizers can comprise an antioxidant (or reducingagent or radical scavengers). The radiolysis stabilizers can compriseone or more antioxidants. The antioxidant can comprise a flavonoid or aderivative thereof. The flavonoid can be polyphenol compounds thatcomprise multiple phenol units. A flavonoid can comprise a 15-carbonstructure. The 15-carbon structure can further comprise two phenyl ringsand a heterocyclic ring. The flavonoid can comprise bioflavonoids,isoflavonoids, or neoflavonoids. The flavonoid can comprise a catechinor a derivative thereof, such as the compounds illustrated in FIG. 1 ,(2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol3-(3,4,5-trihydroxybenzoate ((−) Catechin gallate or CG),(−)-cis-3,3′,4′,5,7-Pentahydroxyflavane (Epi-Catechin or EC),3,4,5-Trihydroxybenzoic acid (Gallic acid),(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate(EpiGallo-Catechin gallate or EGCg),(2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triolor Epigallo-Catechin (EGC), or(2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Gallo-Catechin or GC). The catechins can be administered in human from1 mg/kg to 50 mg/kg, from 5 mg/kg to 40 mg/kg, from 10 mg/kg to 40mg/kg, from 20 mg/kg to 35 mg/kg. The flavonoid can comprise(2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol3-(3,4,5-trihydroxybenzoate ((−) Catechin gallate or CG),3,3′,4′,5,5′,7-Hexahydroxyflavylium chloride,(−)-cis-3,3′,4′,5,7-Pentahydroxyflavane (Epi-Catechin or EC),7-Hydroxy-3-(4′-methoxyphenyl)-4H-benzopyran-4-one,3,4,5-Trihydroxybenzoic acid (Gallic acid), 3,4′,5,7-Tetrahydroxyflavone(Kaempferol), Luteolin,2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one(Rutin hydrate), Quercetin,(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl3,4,5-trihydroxybenzoate(EpiGallo-Catechin gallate or EGCg),(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoate, Epi-Catechin Gallate (ECG),(2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Epigallo-Catechin or EGC), or(2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Gallo-Catechin or GC), or a combination thereof. In some embodiments,the antioxidant is a carotenoid or a derivative thereof. The carotenoidcan be a fat-soluble pigment, such as yellow, orange, or red pigments.The carotenoid can be all-trans-Fucoxanthin, Lycopene, Xanthophyll, Betacarotene, Lycopene, or Lutein.

In some embodiment, a herein described pharmaceutical compositioncomprises an antioxidant that is N-acetyl cysteine, L-Ascorbic acid,N-tert-Butyl-α-phenylnitrone, 3-(3,4-Dihydroxyphenyl)-2-propenoic acid(Caffeic Acid), β-Carotene, Provitamin A,(2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol3-(3,4,5-trihydroxybenzoate ((−) Catechin gallate or CG),1,4,5-Trihydroxycyclohexanecarboxylic acid, trans-4-Hydroxycinnamic acid(p-Coumaric acid), 3,3′,4′,5,5′,7-Hexahydroxyflavylium chloride,Thiocytic Acid (Dihydrolipoic Acid, DHLA),4,4′,5,5′,6,6′-Hexahydroxydiphenic acid 2,6,2′,6′-dilactone (Ellagicacid), (−)-cis-3,3′,4′,5,7-Pentahydroxyflavane (Epi-Catechin or EC),2-Methoxy-4-(2-propenyl) phenol, trans-4-Hydroxy-3-methoxycinnamic acid(Ferulic acid), 7-Hydroxy-3-(4′-methoxyphenyl)-4H-benzopyran-4-one,all-trans-Fucoxanthin, 3,4,5-Trihydroxybenzoic acid (Gallic acid),(2S,3R)-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol ((−)-Gallocatechin), Glutathione,2-(3,4-Dihydroxyphenyl)ethanol, 3,4′,5,7-Tetrahydroxyflavone(Kaempferol), (±)-1,2-Dithiolane-3-pentanoic acid, Luteolin, Lycopene,L-Lysine, Neochlorogenic acid, Oleic acid,trans-3,5,4′-Trihydroxystilbene (Resveratrol),2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one,Rutin hydrate, Selenol-L-methionine, Thiourea, (+)-α-Tocopherol,Xanthophyll, Citric acid (CA), Gentisic acid (GA), Salicylic acid (SA),Erythorbic acid (EA), Phenol, Sodium bisulfite, Butylated hydroxyanisole, Butylated hydroxy toluene, Metabisulfite, Benzyl alcohol,Thymol, Lipoic acid (LA), Thioglycolic acid (TGA), 2,3Dimercaptopropan-1-ol (BAL), Zinc, Selenium, Albumin, Ethanol, Mannitol,Sucrose, Melatonin, Ebselen, Pyruvic acid, Carboxy-PTIO, Trolox,Ebselen, Uric acid, Edaravone, Beta carotene, NADPH, Lycopene, Lutein,Catalase, Estrogen, Estradiol, Estriol, Ubiquinol, Copper, Quercetin,Cortisone, Taurine,(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl3,4,5-trihydroxybenzoate (EpiGallo-Catechin gallate or EGCg),(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoate or Epi-Catechin Gallate (ECG),(2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Epigallo-Catechin or EGC),(2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Gallo-Catechin or GC),(−)-cis-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol3-gallate ((−)-Epigalocatechin-3-O-Gallate), 5-Aminolevulibic Acidhydrate, Ploysorbate 80, Garlic Acid, Sodium L-Ascorbate, HyaluronicAcid, Dextran 60-90, Selenol, and LysaKare. or a combination thereof.Exemplary antioxidants of the present disclosure are further describedin Table 1.

TABLE 1 Exemplary Antioxidants N-Acetyl-L-cysteine Benzyl alcoholL-Ascorbic acid Thymol N-tert-Butyl-α-phenylnitrone Lipoic acid (LA)3-(3,4-Dihydroxyphenyl)-2-propenoic acid (Caffeic Acid) Thioglycolicacid (TGA) β-Carotene, Provitamin A 2,3 Dimercaptopropan-1-ol (BAL)(2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)- Zincbenzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((−) Catechingallate) (from green tea) 1,4,5-Trihydroxycyclohexanecarboxylic acidSelenium trans-4-Hydroxycinnamic acid (p-Coumaric acid) Albumin3,3′,4′,5,5′,7-Hexahydroxyflavylium chloride Ethanol Thiocytic Acid(Dihydrolipoic Acid, DHLA) Mannitol 4,4′,5,5′,6,6′-Hexahydroxydiphenicacid 2,6,2′,6′-dilactone (Ellagic acid) Sucrose(−)-cis-3,3′,4′,5,7-Pentahydroxyflavane (from green tea) Melatonin2-Methoxy-4-(2-propenyl) phenol Ebselentrans-4-Hydroxy-3-methoxycinnamic acid (Ferulic acid) Pyruvic acid7-Hydroxy-3-(4′-methoxyphenyl)-4H-benzopyran-4-one2-(4-Carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazol-1-yloxy-3-oxide potassium salt,2-(4-Carboxyphenyl)- 4,4,5,5-tetramethylimidazoline-1-oxyl-3- oxide(Carboxy-PTIO) Salt all-trans-Fucoxanthin Trolox 3,4,5-Trihydroxybenzoicacid (Gallic acid) Ebselen(2S,3R)-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1(2H)- Uric acidbenzopyran-3,5,7-triol ((−)-Gallocatechin)(from green tea) GlutathioneEdaravone 2-(3,4-Dihydroxyphenyl)ethanol Beta carotene3,4′,5,7-Tetrahydroxyflavone (Kaempferol) Nicotinamide adeninedinucleotide phosphate (NADPH) (±)-1,2-Dithiolane-3-pentanoic acidLycopene Luteolin Lutein Lycopene (from tomato) Catalase Neochlorogenicacid Estrogen Oleic acid Estradiol trans-3,5,4′-Trihydroxystilbene(Resveratrol) Estriol 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3- Ubiquinol[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl[oxymethyl]oxan-2-yl]oxychromen-4-one;hydrateRutin hydrate L-methionine Copper ThioureaQuercetin (+)-α-Tocopherol Cortisone Xanthophyll 2,3-dimercaptosuccinicacid (DMSA) or monisoamyl derivative (MiADMSA) Natural L-amino acids.Alanine, Arginine, Asparagine, Taurine Aspartic acid, Cysteine,Glutamine, Glutamic acid, Glycine, Histidine, Isoleucine, Lysine,Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan,Tyrosine, Valine, and their derivatives Citric acid (CA) Dextran 40Gentisic acid (GA) Dextran 70 Salicylic acid (SA) PEG 3350 Erythorbicacid (EA) PEG 4000 Phenol Polygeline Sodium bisulfite GelofusineButylated hydroxy anisole PLENVU (polyethylene glycol 3350, sodiumsulfate, ascorbic acid, sodium chloride and potassium chloride)Butylated hydroxy toluene Cyclodextrins Glutathione Metabisulfite PEG400 PEG 1000 PEG (e.g., PEG having a number average(−)-Epigallocatechin-3-O-Gallate molecular weight of about 200-8000)5-Aminolevulibic Acid hydrate Ploy sorbate 80 Garlic Acid SodiumL-Ascorbate Hyaluronic Acid Dextran 60-90 Selenol LysaKare

In some embodiments, the radiolysis stabilizers comprise a salt, anester, an amide, an enantiomer, or an acetylation derivative of acompound of Table 1, or a combination thereof.

The radiolysis stabilizers can comprise a vitamin or a derivativethereof. The radiolysis stabilizers can comprise one or more vitamins orderivatives thereof. The vitamin or a derivative thereof can beL-Ascorbic acid, β-Carotene, Provitamin A, (+)-α-Tocopherol, Erythorbicacid (EA), Trolox, or Lutein.

The radiolysis stabilizers can comprise a fatty acid or a derivativethereof. The radiolysis stabilizers can comprise one or more lipids. Thelipids can be fatty acids or derivatives thereof. In some embodiments,the fatty acid is a saturated fatty acid. In some embodiments, the fattyacid is an unsaturated fatty acid. The fatty acid can comprise amono-unsaturated fatty acid. The fatty acid can comprise apoly-unsaturated fatty acid. The fatty acid can comprise a trans-fat.The fatty acid can comprise a C₃ to C₄₀ fatty acid, C₆ to C₃₀ fattyacid, C₆ to C₂₀ fatty acid, and C₆ to C₁₀ fatty acid. In someembodiments, the fatty acid is a C₆ to C₃₀ fatty acid. The fatty acidcan comprise a saturated or unsaturated C₆ to C₃₀ fatty acid. The fattyacid can comprise a saturated or unsaturated C₁₉ to C₂₀ fatty acid. Thefatty acid can comprise a saturated or unsaturated C₁₂ to C₂₆ fattyacid. The fatty acid can comprise oleic acid, Myristoleic acid,Palmitoleic acid, Sapienic acid, Elaidic acid, Vaccenic acid, orLinoleic acid, α-Linolenic acid, or a combination thereof.

In some embodiments, the radiolysis stabilizers comprise a lipid that isa steroid or a derivative thereof. The steroid can be a corticosteroid,such as Estrogen, Estradiol, Estriol, or Cortisone. The steroid can havefour carbon rings. The steroid can be Estrogen, Estradiol, Estriol, orCortisone.

The radiolysis stabilizers can comprise a volume expander. In someembodiments, the volume expander can expand the volume of a liquid, suchas human blood volume. The volume expander can serve as an absorptiveradio-protectant. The volume expander can mimic human serum albumin. Thevolume expander can comprise human albumin. The volume expander cancomprise polymers, such as polyethylene glycol (PEG), a glucose polymer,or polymer mixtures. A glucose polymer can be a Dextran or a saccharide,such as an oligosaccharide. The glucose polymer can have a numberaverage molecular weight from 1 kDa to 40,000,000 kDa, from 5 kDa to1,000,000 kDa, from 10 KDa to 500,000 kDa, from 15 kDa to 1,000 kDa,from 20 kDa to 100 kDa, or from 30 kDa to 50 kDa. The glucose polymercan have an average molecular of about 20-60 kDa, e.g., about 40 kDa.The glucose polymer can be linear or cyclic. The cyclic form glucosepolymer can be cyclic oligosaccharides, such as cyclodextrins. Thecyclodextrins can comprise a macrocyclic ring of glucose subunits joinedby α-1,4 glycosidic bonds. The macrocyclic ring can comprise 6 to 8glucose subunits, such as, α (alpha)-cyclodextrin, β(beta)-cyclodextrin, and γ (gamma)-cyclodextrin. The polymer mixture,such as an artificial colloid, can comprise the glucose polymer from0.001 wt % to 80% wt %. The polymer mixture can comprise the glucosepolymer from 0.1 wt % to 50% wt %. The polymer mixture can comprise theglucose polymer from 1 wt % to 20% wt %. The polymer mixture can be amixture comprise the glucose polymer from 5 wt % to 15% wt %. Thepolymer mixture can comprise from 0.1% wt to 15% wt glucose polymer, orfrom 1% wt to 10% glucose polymer. The Dextran can be Dextran 40 andDextran 70. The Dextran can have a number average molecular weight ofabout 5 to 100 kDa. The Dextran can have a number average molecularweight of about 40 to 70 kDa. The Dextran can have a number averagemolecular weight of 40, 60, or 70 kDa. Dextran 40 can be provided as aDextran 40 mixture, such as a 10% Dextran 40 solution in 0.9% sodiumchloride in an infusion bag. The Dextran 40 mixture can comprise from0.1% wt to 15% wt Dextran 40, or from 1% wt to 10% Dextran 40. TheDextran 40 mixture can have a total osmolality from 300 mOsmol/L to 450mOsmol/L. The Dextran 40 mixture can have a total osmolality from 350mOsmol/L to 420 mOsmol/L. The Dextran 40 mixture can have a totalosmolality from 380 mOsmol/L to 400 mOsmol/L. The Dextran 40 mixture canhave a total osmolality of 390 mOsmol/L. The polymer can be aPolyethylene glycol (PEG), such as PEG 4000, PEG 3350. In someembodiments, the PEG has a number average molecular weight of about 200to 20,000, 1000 to 10,000, 2000 to 8000, 3000 to about 5000, or 3000 to4000. The polymer mixture can comprise PEG, such as PLENVU, acombination of PEG 3350, sodium ascorbate, sodium sulfate, ascorbicacid, sodium chloride and potassium chloride. The polymer can be agelatin or a modified gelatin, such as polygeline and succinylatedgelatin. The polygeline can have a number average molecular weight from5 kDa to 50 kDa, from 10 kDa to 45 kDa, from 20 KDa to 50 kDa, from 30kDa to 40 kDa. The polygeline can have an average molecular of 35 kDa.The polymer mixture can be a mixture containing polygeline. A mixturecomprising polygeline, such as Haemaccel, can also contain calciumchloride, potassium chloride and or sodium chloride. The polymer mixturecan comprise modified fluid gelatin, such as succinylated gelatin. Thepolymer mixture can be a solution, such as Gelofusine. Gelofusine cancomprise 4% w/v succinylated gelatin.

The radiolysis stabilizers can comprise a carbohydrate or a derivativethereof. The carbohydrate can be a saccharide. The saccharide can be amonosaccharide. The saccharide can be a disaccharide, anoligosaccharide, or a polysaccharide. Exemplary disaccharides include amannitol and a sucrose. The polysaccharide can be a Dextran such asDextran 40 and Dextran 70. The Dextran can have a molecular weight ofabout 10-200, 20-100, 30-50, or 40-70 kDa. The polysaccharide can have anumber average molecular weight from 5 kDa to 1,000,000 kDa, from 10 KDato 500,000 kDa, from 15 kDa to 1,000 kDa, from 20 kDa to 100 kDa, orfrom 30 kDa to 80 kDa. The oligosaccharide can be a cyclicoligosaccharide, such as cyclodextrin. The cyclodextrin can comprise amacrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds.The macrocyclic ring can comprise 6 to 8 glucose subunits, such as, α(alpha)-cyclodextrin, β (beta)-cyclodextrin, and γ (gamma)-cyclodextrin.The polysaccharide can be a Dextran. The carbohydrate can be Mannitol,Sucrose, Dextran (e.g., Dextran 40, Dextran 70), or Cyclodextrins(α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin), such as2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) orsulfobutylether-β-Cyclodextrin (SEB-β-CD).

Free Metal Chelator

The one or more stabilizing agents can comprise a free metal chelator.The one or more stabilizing agents can comprise two or more free metalchelators. In some embodiments, the free metal chelator is not attachedto the targeting ligand. The one or more stabilizing agents can comprisea first and a second free metal chelator. In some embodiments, the molarratio of the first and the second free metal chelator is from 1:100,000to 100,000:1, from 1:1,000 to 1,000:1, from 1:100 to 100:1, from 1:20 to20:1, from 1:10 to 10:1, and from 1:5 to 5:1. In some embodiments, themolar ratio of the first and the second free metal chelator is from 1:5to 5:1. The free metal chelator can be present in theradiopharmaceutical composition at about 0.001 wt % to about 10 wt %.The free metal chelator can be present in the radiopharmaceuticalcomposition at about 0.0001 wt % to about 20 wt %, 0.001 wt % to about10 wt %, 0.01 wt % to about 5 wt %, about 0.05 wt % to about 2 wt %, orabout 0.1 wt % to about 1 wt %. The free metal chelator can be presentin the radiopharmaceutical composition at about 0.01 wt % to about 5 wt%. The free metal chelator can be present in the radiopharmaceuticalcomposition at about 0.05 wt % to about 2 wt %. The free metal chelatorcan be present in the radiopharmaceutical composition at about 0.1 wt %to about 1 wt %. The free metal chelator can also be present in theradiopharmaceutical composition at a concentration of from 0.0001 to5,000 mg/mL. The free metal chelator can also be present in theradiopharmaceutical composition at a concentration of from 0.1 to 500mg/mL. The free metal chelator can also be present in theradiopharmaceutical composition at a concentration of from 0.01 to 50mg/mL. The free metal chelator can also be present in theradiopharmaceutical composition at a concentration of from 0.1 to 5mg/mL. The free metal chelator can also be present in theradiopharmaceutical composition at a concentration of from 0.5 to 2mg/mL.

The free metal chelator can be a linear or cyclic. The linear free metalchelator, such as Ethylenediaminetetraacetic acid (EDTA) andDiethylenetriaminepentaacetic acid (DTPA), can be a heavy metalpoisoning antidote or a free heavy metal scavenger. The DTPA can bepresent in the radiopharmaceutical composition at a concentration from0.001 mg/mL to 2.5 mg/mL, from 0.01 mg/mL to 5 mg/mL, from 0.02 mg/mL to3 mg/mL, from 0.04 mg/mL to 1 mg/mL, or from 0.05 mg/mL to 0.1 mg/mL. Insome embodiments, the free metal chelator (such as DTPA) is present inthe radiopharmaceutical composition at a concentration of about 0.05mg/mL. In some embodiments, the free metal chelator (such as DTPA) ispresent in the radiopharmaceutical composition at a concentration ofabout 0.01 to 0.1 mg/mL. In some embodiments, the free metal chelator(such as DTPA) is present in the radiopharmaceutical composition at aconcentration of about 0.02 to 0.07 mg/mL. In some embodiments, the freemetal chelator is DTPA and is present in the radiopharmaceuticalcomposition at a concentration from 0.01 mg/mL to 5 mL/mL. In someembodiments, the free metal chelator is DTPA and is present in theradiopharmaceutical composition at a concentration from 0.02 mg/mL to2.5 mg/mL. In some embodiments, the free metal chelator is DTPA and ispresent in the radiopharmaceutical composition at a concentration from0.04 mg/mL to 1 mg/mL. In some embodiments, the free metal chelator isDTPA and is present in the radiopharmaceutical composition at aconcentration from 0.01 to 0.25 mg/mL. In some embodiments, the freemetal chelator is DTPA and is present in the radiopharmaceuticalcomposition at a concentration from 0.02 to 0.125 mg/mL. In someembodiments, the free metal chelator is DTPA and is present in theradiopharmaceutical composition at a concentration from 0.04 to 0.06mg/mL. In some embodiments, the free metal chelator is DTPA and ispresent in the radiopharmaceutical composition at a concentration of0.05 mg/mL. The free metal chelator can also prevent potentialhepatoxicity caused by free radioactive metal ion when administered intoa subject, such as a human subject. The cyclic free metal chelator canbe a macrocyclic free metal chelator, such as1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA)2,2′,2″,2′″-(1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrayl)tetraaceticacid (DOTA). The macrocyclic free metal chelator can have strongchelation ability and used in lower concentration. The free metalchelator can comprise Ethylenediaminetetraacetic acid (EDTA),Diethylenetriaminepentaacetic acid (DTPA),2-S-(4-Isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triaceticacid (NOTA), Triethylenetetramine (TETA), 1, 4, 7, 10,13-pentaazacyclopentadecane-N, N′,N″, N′″, N″″-pentaacetic acid (PEPA),TETPA,2,2′,2″-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triaceticacid (DOTA-GA), 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid (DOTP), Deferoxamine (DFO), N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED),1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid)(DOTP),6,6′-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinicacid (Macropa), Meso-2,3-dimercaptosuccinic acid (DMSA),Dimercaptopropane sulfonate (DMPS), Dihydrolipoic acid (DHLA), Lipoicacid (LA), Thioglycolic acid (TGA), 2,3 Dimercaptopropan-1-ol (BAL), ora combination thereof. The free metal chelator can comprise EDTA, DTPA,or Macropa. Exemplary free metal chelators of the present disclosure arefurther described in Table 2.

TABLE 2 Exemplary Free Metal Chelators Ethylenediaminetetraacetic acid(EDTA) N, N-bis(2-hydroxybenzypethylenediamine-N,N- diacetic acid (HBED)Diethylenetriaminepentaacetic acid (DTPA)1,4,7,10-Tetraazacyclododecane-1,4,7,10- tetra(methylene phosphonicacid) (DOTP) 1,4,7-Triazacyclononane-1,4,7-triacetic acid6,6′-((1,4,10,13-tetraoxa-7,16- (NOTA) diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinic acid (Macropa)2,2′,2″,2″-(1,4,7,10-Tetraazacyclododecane- Meso-2,3-dimercaptosuccinicacid (DMSA) 1,4,7,10-tetrayl)tetraacetic acid (DOTA)Triethylenetetramine (TETA) Dimercaptopropane sulfonate (DMPS) 1, 4, 7,10, 13-pentaazacyclopentadecane-N, N′, N″, Dihydrolipoic acid (DHLA) N″,N″-pentaacetic acid (PEPA) TETPA Lipoic acid (LA)2,2′,2″-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)- Thioglycolic acid (TGA)1,4,7,10-tetraazacyclododecane-1,4,7-triyptriacetic acid (DOTA-GA)1,4,7,10-Tetraazacyclododecane-1,4,7,10- 2,3 Dimercaptopropan-1-ol (BAL)tetra(methylene phosphonic acid (DOTP) Deferoxamine (DFO)pH Stabilizer

In some embodiments, stabilities of the described radiopharmaceuticalcompositions can vary at different pH values. When pH fails out ofcertain range, leakage of the radioactive metal may also affectradiochemical purity of the formulated dose and shorten its shelf-life.Accordingly, in some embodiments, the one or more stabilizing agents cancomprise pH stabling buffers in addition to the radiolysis protectantsand/or free metal chelating agents. Exemplary pH stabilizers includesodium acetate/acetic acid and sodium L-ascorbate/L-ascorbic acidaqueous buffer.

The one or more stabilizing agents can comprise one or more pHstabilizers. The one or more pH stabilizers can function as a pH buffer.The one or more pH stabilizer can function as a pH buffer. The one ormore pH stabilizer can comprise an organic acid. The organic acid cancomprise an acetic acid, fumaric acid, ascorbic acid, propionic acid,benzene sulfonic acid, carbonic acid, citrate acid, aspartic acid,maleic acid, methane sulfonic acid, or tartaric acid. The one or more pHstabilizer can comprise an inorganic acid, which can further comprise ahydrobromic acid, hydrochloric acid, phosphoric acid, boric acid, orsulfuric acid. The one or more pH stabilizer can comprise a base. Thebase can comprise tromethamine (Tris), ammonium hydroxide,diethanolamine, or sodium hydroxide. The one or more pH stabilizers cancomprise an amino acid or a salt thereof. The one or more pH stabilizerscan comprise glycine, lysine, arginine, histidine, or a salt thereof.The one or more pH stabilizers can comprise an alkaline salt. Thealkaline salt can comprise sodium acetate, sodium ascorbate, sodiumbenzoate, sodium bicarbonate, sodium carbonate, tribasic sodiumphosphate acid, dibasic sodium phosphate acid, monobasic sodiumphosphate acid, sodium tartrate, sodium lactate, sodium succinate, ordisodium succinate. The sodium ascorbate be present in theradiopharmaceutical composition at a concentration of from about 50 mMto 200 mM. The one or more pH stabilizers can comprise an acid salt. Theacid salt can be ammonium sulfate. The one or more pH stabilizers cancomprise Sodium acetate, Sodium ascorbate, Ascorbic acid, Acetic acid,Fumaric acid propionic acid, ascorbic acid, ammonium sulfate, ammoniumhydroxide, arginine, aspartic acid, benzene sulfonic acid, sodiumbenzoate, sodium bicarbonate, boric acid, sodium carbonate, carbonicacid, diethanolamine, citrate acid, hydrobromic acid, glycine,histidine, sodium lactate, (1)-lysine, maleic acid, methane sulfonicacid, phosphate acid, monobasic sodium phosphate acid, tribasic sodiumphosphate acid, dibasic sodium phosphate acid, sodium hydroxide,sodium/disodium succinate, sulfuric acid, sodium tartrate, tartaricacid, tromethamine (tris), or a combination thereof. Exemplary pHstabilizers of the present disclosure are further described in Table 3.

TABLE 3 Exemplary pH Stabilizers Sodium acetate Citrate acid Acetic acidHydrobromic acid Sodium L-ascorbate Glycine L-Ascorbic acid HistidineFumaric acid Sodium lactate Propionic acid (L)-Lysine Ammonium sulfateMaleic acid Ammonium hydroxide Methane sulfonic acid Arginine Phosphateacid Aspartic acid Monobasic sodium phosphate acid Benzene sulfonic acidTribasic sodium phosphate acid Sodium benzoate Dibasic sodium phosphateacid Sodium bicarbonate Sodium hydroxide Boric acid Sodium/disodiumsuccinate Sodium carbonate, Sulfuric acid Carbon dioxide Sodium tartrateDiethanolamine Tartaric acid Tromethamine (Tris)

In some embodiments, the pH stabilizers can reduce the pH changes andmaintain the radiopharmaceutical purity, which reduces the decompositionof the conjugate and thereby extending the shelf-life of theradiopharmaceutical compositions described herein. The one or morestabilizing agents can comprise a pH stabilizer. The one or morestabilizing agents can comprise two or more pH stabilizers. The one ormore stabilizing agents can comprise a first and a second pHstabilizers. In some embodiments, the molar ratio of the first and thesecond pH stabilizer is from 1:100,000 to 100,000:1, from 1:1,000 to1,000:1, from 1:100 to 100:1, from 1:20 to 20:1, from 1:10 to 10:1, andfrom 1:5 to 5:1. In some embodiments, the molar ratio of the first andthe second pH stabilizer is from 1:5 to 5:1. The pH stabilizer can bepresent in the radiopharmaceutical composition at about 0.001 wt % toabout 10 wt %. The pH stabilizer can be present in theradiopharmaceutical composition at about 0.0001 wt % to about 20 wt %,0.001 wt % to about 10 wt %, 0.01 wt % to about 5 wt %, about 0.05 wt %to about 2 wt %, or about 0.1 wt % to about 1 wt %. The pH stabilizercan be present in the radiopharmaceutical composition at about 0.01 wt %to about 5 wt %. The pH stabilizer can be present in theradiopharmaceutical composition at about 0.05 wt % to about 2 wt %. ThepH stabilizer can be present in the radiopharmaceutical composition atabout 0.1 wt % to about 1 wt %. The pH stabilizer can also be present inthe radiopharmaceutical composition at a concentration of from about 1μM, 10 μM, 0.1 mM, 1 mM, 5 mM, 10 mM, 25 mM, 50 mM, or 75 mM to about 80mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 250 mM, 500 mM, 1 M, 2 M, 3M, 4 M, or 5 M. The pH stabilizer can be present in theradiopharmaceutical composition at a concentration of from about 1 μM to5 M. The pH stabilizer can be present in the radiopharmaceuticalcomposition at a concentration of from about 10 μM to 1 M. The pHstabilizer can be present in the radiopharmaceutical composition at aconcentration of from about 0.1 mM to 500 mM. The pH stabilizer can bepresent in the radiopharmaceutical composition at a concentration offrom about 10 mM to 500 mM. The pH stabilizer can be present in theradiopharmaceutical composition at a concentration of from about 50 mMto 250 mM. The pH stabilizer can be present in the radiopharmaceuticalcomposition at a concentration of from about 80 mM to 200 mM. The pHstabilizer can be present in the radiopharmaceutical composition at aconcentration of from about 80 mM to 120 mM. The pH stabilizer can alsobe present in the radiopharmaceutical composition at a concentration offrom 0.0001 to 5,000 mg/mL. The pH stabilizer can also be present in theradiopharmaceutical composition at a concentration of from 0.1 to 500mg/mL. The pH stabilizer can also be present in the radiopharmaceuticalcomposition at a concentration of from 0.01 to 50 mg/mL. The pHstabilizer can also be present in the radiopharmaceutical composition ata concentration of from 0.1 to 5 mg/mL. The pH stabilizer can also bepresent in the radiopharmaceutical composition at a concentration offrom 0.5 to 2 mg/mL. In some embodiments, the pH stabilizer comprisessodium L-ascorbate. In some embodiments, the pH stabilizer comprisessodium ascorbate (e.g., sodium L-ascorbate) and is present in theradiopharmaceutical composition at a concentration of 1 mM to 10 M. Insome embodiments, the pH stabilizer comprises sodium L-ascorbate and ispresent in the radiopharmaceutical composition at a concentration of 10mM to 1 M. In some embodiments, the pH stabilizer comprises sodiumL-ascorbate and is present in the radiopharmaceutical composition at aconcentration of 20 mM to 500 mM. In some embodiments, the pH stabilizercomprises sodium L-ascorbate and is present in the radiopharmaceuticalcomposition at a concentration of 40 mM to 250 mM. In some embodiments,the pH stabilizer comprises sodium L-ascorbate and is present in theradiopharmaceutical composition at a concentration of 80 mM to 125 mM.In some embodiments, the pH stabilizer comprises sodium L-ascorbate andis present in the radiopharmaceutical composition at a concentration of90 mM to 110 mM. In some embodiments, the pH stabilizer comprises sodiumL-ascorbate and is present in the radiopharmaceutical composition at aconcentration of 100 mM.

In some embodiments, the sodium ascorbate is present in theradiopharmaceutical composition at a concentration of 1 mM to 10 M. Insome embodiments, the sodium ascorbate is present in theradiopharmaceutical composition at a concentration of 10 mM to 1 M. Insome embodiments, the sodium ascorbate is present in theradiopharmaceutical composition at a concentration of 20 mM to 500 mM.In some embodiments, the sodium ascorbate is present in theradiopharmaceutical composition at a concentration of 40 mM to 250 mM.In some embodiments, the sodium ascorbate is present in theradiopharmaceutical composition at a concentration of 80 mM to 125 mM.In some embodiments, the sodium ascorbate is present in theradiopharmaceutical composition at a concentration of 90 mM to 110 mM.In some embodiments, the sodium ascorbate is present in theradiopharmaceutical composition at a concentration of about 100 mM. Insome embodiments, the sodium ascorbate is present in theradiopharmaceutical composition at a concentration of about 1 mg/mL to100 mg/mL. In some embodiments, the sodium ascorbate is present in theradiopharmaceutical composition at a concentration of about 5 mg/mL to50 mg/mL. In some embodiments, the sodium ascorbate is present in theradiopharmaceutical composition at a concentration of about 10 mg/mL to30 mg/mL. In some embodiments, the sodium ascorbate is present in theradiopharmaceutical composition at a concentration of 18.5±4.63 mg/mL.In some embodiments, the sodium ascorbate is present in theradiopharmaceutical composition at a concentration of 18.5±5 mg/mL. Insome embodiments, the sodium ascorbate is present in theradiopharmaceutical composition at a concentration of 18.5±10 mg/mL. Insome embodiments, the sodium ascorbate is present in theradiopharmaceutical composition at a concentration of about 18.5 mg/mL.In some embodiments, the sodium ascorbate is sodium L-ascorbate.

Radiopharmaceutical compositions described herein can have a suitable pHvalue. The one or more pH stabilizers can be configured to maintain a pHof the radiopharmaceutical composition at about 3 to about 9, about 4 toabout 8, or about 5 to about 7. The pH of the radiopharmaceuticalcomposition can be within a range of about 3 to about 9. The pH of theradiopharmaceutical composition can be within a range of about 4 toabout 8. The pH of the radiopharmaceutical composition can be within arange of about 5 to about 7. In some embodiments, the pH of theradiopharmaceutical composition is from about 4.0 to about 9.0, fromabout 4.5 to about 8.5, from about 5.0 to about 8.0, from about 5.5 toabout 7.75, from about 6.0 to about 7.5, from about 6.5 to about 7.25,from 6.75 to about 7.25. The pH of the radiopharmaceutical compositioncan be about 4.0 to about 9.0. The pH of the radiopharmaceuticalcomposition can be about 4.5 to about 8.5. The pH of theradiopharmaceutical composition can be about 5.0 to about 8.0. The pH ofthe radiopharmaceutical composition can be about 5.0 to about 7.0. ThepH of the radiopharmaceutical composition can be about 5.5 to about 6.5.The pH of the radiopharmaceutical composition can be about 5.5 to about6. The pH of the radiopharmaceutical composition can be about 5.6 toabout 5.8. The pH of the radiopharmaceutical composition can be about5.75 to about 5.85. The pH of the radiopharmaceutical composition can beabout 5.5 to about 7.75. The pH of the radiopharmaceutical compositioncan be about 6.0 to about 7.5. The pH of the radiopharmaceuticalcomposition can be about 6.5 to about 7.25. The pH of theradiopharmaceutical composition can be about 6.75 to about 7.25. In someembodiments, the pH of the radiopharmaceutical composition is about 7.In some embodiments, the pH of the radiopharmaceutical composition isabout 5.5. In some embodiments, the pH of the radiopharmaceuticalcomposition is about 5.6. In some embodiments, the pH of theradiopharmaceutical composition is about 5.7. In some embodiments, thepH of the radiopharmaceutical composition is about 5.8. In someembodiments, the pH of the radiopharmaceutical composition is about 5.9.In some embodiments, the pH of the radiopharmaceutical composition isabout 6. In some embodiments, the pH of the radiopharmaceuticalcomposition is about 6.1. In some embodiments, the pH of theradiopharmaceutical composition is about 6.2.

The radiopharmaceutical composition can comprise one or more radiolysisstabilizers, one or more free metal chelators, and/or one or more pHstabilizers. The radiopharmaceutical composition can comprise one ormore radiolysis stabilizers. The radiopharmaceutical composition cancomprise one or more free metal chelators. The radiopharmaceuticalcomposition can comprise one or more pH stabilizers.

In some embodiments, a radiopharmaceutical composition described hereincomprises: (a) a conjugate (e.g., ²²⁵Ac-DOTA-TATE or ²²⁵Ac-DOTA-TOC),wherein the conjugate is present in the radiopharmaceutical compositionat a concentration equivalent to about 10 to 45 mCi/L (e.g., 30 mCi/L);(b) a pH stabilizer, wherein the pH stabilizer is present in theradiopharmaceutical composition at a concentration of about 80 to about120 mM; (c) optionally a radiolysis stabilizer, wherein the radiolysisstabilizer is present in the radiopharmaceutical composition atconcentration of about 1 wt % to about 10 wt %; (d) a free metalchelator, therein the free metal chelator is present in theradiopharmaceutical composition at concentration of about 0.01 mg/mL toabout 1 mg/mL; and (e) an aqueous vehicle. In some embodiments, theconjugate is present in the radiopharmaceutical composition at aconcentration equivalent to about 15 to 45 mCi/L. In some embodiments,the conjugate is present in the radiopharmaceutical composition at aconcentration equivalent to about 10 to 35 mCi/L. In some embodiments,the conjugate is present in the radiopharmaceutical composition at aconcentration equivalent to about 10 to 25 mCi/L. In some embodiments,the conjugate is present in the radiopharmaceutical composition at aconcentration equivalent to about 12 to 23 mCi/L. In some embodiments, aradiopharmaceutical composition described herein comprises: (a) aconjugate (e.g., ²²⁵Ac-DOTA-TATE or ²²⁵Ac-DOTA-TOC), wherein theconjugate is present in the radiopharmaceutical composition at aconcentration equivalent to about 10 to 45 mCi/L; (b) a pH stabilizer,wherein the pH stabilizer is sodium L-ascorbate and is present in theradiopharmaceutical composition at a concentration of about 80 to about120 mM; (c) optionally a radiolysis stabilizer, wherein the radiolysisstabilizer is Dextran 40 and is present in the radiopharmaceuticalcomposition at a concentration of about 1 wt % to about 10 wt %; (d) afree metal chelator, wherein the free metal chelator is DTPA and ispresent in the radiopharmaceutical composition at a concentration ofabout 0.01 mg/mL to about 1 mg/mL; and (e) an aqueous vehicle, whereinthe aqueous vehicle is saline solution. In some embodiments, theconjugate is present in the radiopharmaceutical composition at aconcentration equivalent to about 15 to 45 mCi/L. In some embodiments,the radiopharmaceutical composition comprises (a) the conjugate, whereinthe conjugate is present in the radiopharmaceutical composition at aconcentration equivalent to about 25 to 35 mCi/L; (b) a pH stabilizer,wherein the pH stabilizer is sodium L-ascorbate and is present in theradiopharmaceutical composition at a concentration of about 90-110 mM;(c) a radiolysis stabilizer, wherein the radiolysis stabilizer isDextran 40 and is present in the radiopharmaceutical composition at aconcentration of about 4-6 wt %; (d) a free metal chelator, wherein thefree metal chelator is DTPA and is present in the radiopharmaceuticalcomposition at a concentration of about 0.01-0.03 mg/mL; and (e) anaqueous vehicle, wherein the aqueous vehicle is sodium chloride salinesolution at a concentration of about 0.9% w/w. In some embodiments, theradiopharmaceutical composition comprises (a) the conjugate, wherein theconjugate is present in the radiopharmaceutical composition at aconcentration equivalent to about 10 to 25 mCi/L; (b) a pH stabilizer,wherein the pH stabilizer is sodium L-ascorbate and is present in theradiopharmaceutical composition at a concentration of about 90-110 mM;(c) a radiolysis stabilizer, wherein the radiolysis stabilizer isDextran 40 and is present in the radiopharmaceutical composition at aconcentration of about 4-6 wt %; (d) a free metal chelator, wherein thefree metal chelator is DTPA and is present in the radiopharmaceuticalcomposition at a concentration of about 0.01-0.03 mg/mL; and (e) anaqueous vehicle, wherein the aqueous vehicle is sodium chloride salinesolution at a concentration of about 0.9% w/w. In some embodiments, theradiopharmaceutical composition comprises (a) the conjugate, wherein theconjugate is present in the radiopharmaceutical composition at aconcentration equivalent to about 25 to 35 mCi/L; (b) a pH stabilizer,wherein the pH stabilizer is sodium L-ascorbate and is present in theradiopharmaceutical composition at a concentration of about 90-110 mM;(c) a free metal chelator, wherein the free metal chelator is DTPA andis present in the radiopharmaceutical composition at a concentration ofabout 0.04-0.06 mg/mL; and (d) an aqueous vehicle, wherein the aqueousvehicle is sodium chloride saline solution at a concentration of about0.9% w/w. In some embodiments, the radiopharmaceutical compositioncomprises (a) the conjugate, wherein the conjugate is present in theradiopharmaceutical composition at a concentration equivalent to about10 to 25 mCi/L; (b) a pH stabilizer, wherein the pH stabilizer is sodiumL-ascorbate and is present in the radiopharmaceutical composition at aconcentration of about 90-110 mM; (c) a free metal chelator, wherein thefree metal chelator is DTPA and is present in the radiopharmaceuticalcomposition at a concentration of about 0.04-0.06 mg/mL; and (d) anaqueous vehicle, wherein the aqueous vehicle is sodium chloride salinesolution at a concentration of about 0.9% w/w.

Additional Excipients

Radiopharmaceutical compositions described herein can compriseadditional excipients. In some embodiments, the additional excipientsinclude excipients suitable for a formulation configured for intravenousadministration.

In some embodiments, the radiopharmaceutical composition describedherein comprises a surfactant. “Surfactants” can be defined assurface-active amphiphilic compounds such as block copolymers. They canbe referred to as wetting agents. Non-limiting examples of surfactantsinclude a poloxamer (e.g., poloxamer 188), sodium lauryl sulfate,Desoxycholate sodium, Egg yolk phospholipid, Gelatin, HydrolyzedLecithin, Polyoxyethylated fatty acid, Polysorbate 80 (Tween 80),Polysorbate 20 (Tween 20), PEG 40 castor oil (polyoxyl 40 castor oil,castor oil POE-40, Croduret 40, polyoxyethylene 40 castor oil, ProtachemCA-40), PEG 60 castor oil (Cremophor RH 60, hydrogenated castor oilPOE-60, Protachem CAH-60), Poloxamer 188 (Pluronic F68), Povidone(Polyvinyl pyrrolidone, Crosspovidone), Sodium dodecyl sulfate (Nalauryl sulfate), Aluminum monostearate, Sorbitol, and Triton X-100(Octoxynol-9).

The surfactant used in the present disclosure can comprise a non-ionicsurfactant. A non-ionic surfactant has no charged groups in its head.Exemplary nonionic surfactants include, without limitation, fattyalcohols, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and oleylalcohol. Exemplary nonionic surfactants include, but are not limited to,polyethylene glycol alkyl ethers (such as octaethylene glycolmonododecyl ether, pentaethylene glycol monododecyl ether),polypropylene glycol alkyl ethers, glucoside alkyl ethers (such as decylglucoside, lauryl glucoside, octyl glucoside), polyethylene glycoloctylphenyl ethers (such as Triton X-100), polyethylene glycolalkylphenyl ethers (such as nonoxynol-9), glycerol alkyl esters (such asglyceryl laurate), polyoxyethylene glycol sorbitan alkyl esters (such aspolysorbate), sorbitan alkyl esters (such as Spans), cocamide MEA,cocamide DEA, dodecyldimethylamine oxide, block copolymers ofpolyethylene glycol and polypropylene glycol (such as poloxamers), andpolyethoxylated tallow amine (POEA). In some embodiments, the surfactantis a non-ionic surfactant that comprises polyethylene glycol. In someembodiments, the surfactant is a block copolymer of polyethylene glycoland polypropylene glycol.

In some embodiments, the non-ionic surfactant has a number averagemolecular weight of from about from about 1000 to about 100,000 Da, 2000to about 20,000 Da, from about 4000 to about 15,000 Da, from about 6000to about 12,000 Da, or from about 7000 to about 10,000 Da. In someembodiments, the non-ionic surfactant has a number average molecularweight of from about 7000 to about 10,000 Da. In some embodiments, thenon-ionic surfactant has an ethylene glycol content of from about 30 wt% to about 99 wt %, from about 50 wt % to about 95 wt %, from about 60wt % to about 95 wt %, from about 75 wt % to about 90 wt %, or fromabout 80 wt % to about 85 wt %. In some embodiments, the non-ionicsurfactant has an ethylene glycol content of from about 80 wt % to about85 wt %.

The surfactant used in the present disclosure can comprise a cationicsurfactant. Cationic surfactants include pH-dependent primary,secondary, or tertiary amines such as octenidine dihydrochloride; andpermanently charged quaternary ammonium salts such as cetrimoniumbromide (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride(BAC), benzethonium chloride (BZT), dimethyldioctadecylammoniumchloride, and dioctadecyldimethylammonium bromide (DODAB).

The surfactant used in the present disclosure can comprise an anionicsurfactant. Anionic surfactants contain anionic functional groups attheir head, such as sulfate, sulfonate, phosphate, and carboxylates.Exemplary anionic surfactants include, but are not limited to, ammoniumlauryl sulfate, sodium lauryl sulfate (sodium dodecyl sulfate, SLS, orSDS), and the related alkyl-ether sulfates sodium laureth sulfate(sodium lauryl ether sulfate or SLES), sodium myreth sulfate, docusate(dioctyl sodium sulfosuccinate), perfluorooctanesulfonate (PFOS),perfluorobutanesulfonate, alkyl-aryl ether phosphates, and alkyl etherphosphates.

The surfactant used in the present disclosure can be a zwitterionicsurfactant. Zwitterionic (amphoteric) surfactants refer to those havingcationic and anionic centers attached to the same molecule. Exemplaryzwitterionic surfactants include, without limitation, phospholipidsphosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, andsphingomyelins.

In some embodiments of the present disclosure, the concentration of asurfactant described herein in the described liquid pharmaceuticalcomposition is 0.1% to 15% by weight. In some embodiments, theconcentration of the surfactant is 0.5%-8% by weight in the liquidpharmaceutical composition. In some embodiments, the concentration ofthe surfactant is 0.5%-6% by weight in the liquid pharmaceuticalcomposition. In some embodiments, the concentration of the surfactant is0.25%-8% by weight in the liquid pharmaceutical composition. In someembodiments, the concentration of the surfactant is 0.75%-8% by weightin the liquid pharmaceutical composition. In some embodiments, theconcentration of the surfactant is 0.5%-5% by weight in the liquidpharmaceutical composition. In some embodiments, the concentration ofthe surfactant is 0.75%-10% by weight in the liquid pharmaceuticalcomposition. In some embodiments, the concentration of the surfactant is0.75%-6% by weight in the liquid pharmaceutical composition. In someembodiments, the concentration of the surfactant is 0.75%-4% by weightin the liquid pharmaceutical composition. In some embodiments, theconcentration of the surfactant is 1%-4% by weight in the liquidpharmaceutical composition. In some embodiments, the concentration ofthe surfactant is 1%-6% by weight in the liquid pharmaceuticalcomposition. In some embodiments, the concentration of the surfactant is5%-10% by weight in the liquid pharmaceutical composition. In someembodiments, the concentration of the surfactant is 5%-15% by weight inthe liquid pharmaceutical composition. In some embodiments, theconcentration of the surfactant is 10%-25% by weight in the liquidpharmaceutical composition.

In some embodiments, the radiopharmaceutical composition describedherein comprises a tonicity adjusting agent. Exemplary tonicityadjusting agents include dextrose, glycerin, mannitol, potassiumchloride and sodium chloride.

In some embodiments, the radiopharmaceutical composition describedherein comprises a special additive. In some embodiments, the specialadditive comprises Acetyl tryptophan, Aluminum hydroxide, Aluminumphosphate, Aluminum potassium sulfate, Amino acids (leucine, isoleucine,lysine (as acetate or HCl salt), valine, phenylalanine, threonine,tryptophan, alanine, aspartic acid, glutamic acid, proline, serine,tyrosine, taurine), ε-Aminocaproic acid, Calcium D-saccharate, Caprylatesodium, 8-Chlorotheophylline, Creatine, Creatinine, Cholesterol,Cholesteryl sulfate sodium, Cyclohexanedione dioxime, Diethanolamine,Distearyl phosphatidylcholine, Distearyl phosphatidylglycerol,L-alpha-dimyristoylphosphatidylcholine,L-alpha-dimyristoylphosphatidylglycerol, Dioleoylphosphatidylcholine(DOPC), Dipalmitoylphosphatidylglycerol (DPPG), (R)-hexadecanoic acid,1-[(phosphonoxy)methyl]-1,2-ethanediyl ester, monosodium salt (DPPA),(R)-4-hydroxy-N,N,N-trimethyl-10-oxo-7-[(1oxohexadecyl)oxy]-3,4,9-trioxa-4-phosphapentacosan-1-aminium,4-oxide, inner salt (DPPC),(R)-[6-hydroxy-6-oxido-9-[(1-oxohexadecyl)oxy]-5,7,11-trioxa-2aza-6-phosphahexacos-1-yl]-ω-methoxypoly(ox-1,2-ethanediyl),monosodium salt (MPEG5000 DPPE), MPEG-distearoyl phosphoethanolamine,Ethyl lactate, Ethylenediamine, L-Glutamate sodium, Hyaluronate sodium,Hydrogenated soy phosphatidylcholine, Iron ammonium citrate, Lacticacid, D,L-lactic and glycolic acid copolymer, Meglumine, Methyl boronicacid, Niacinamide, Paraben methyl, Phosphatidylglycerol, egg (EPG),Potassium sodium tartrate, Protamine (as sulfate), Simethicone,Saccharin sodium, Sodium D-gluconate, Sodium hypochlorite, Sodiumsulfate, Stannous chloride, Sulfosalicylate disodium, Tin chloride(stannous and stannic), Tri-n-butyl phosphate, Tricaprylin, Triolein,von Willebrand factor, Zinc, Zinc acetate, Zinc carbonate, Zinc oxide,or a combination thereof.

In some embodiments, the radiopharmaceutical composition describedherein comprises a suspending agent. Non-limiting examples of suspendingagents include Carboxy methyl cellulose (CMC), Croscarmellose sodium,sodium CMC, xanthan gum, hydroxyl ethyl cellulose (HEC), hydroxyl propylmethyl cellulose (HPMC), and Avicel CL-611. Further exemplary suspendingagents include carboxymethylcellulose (sodium and other salts),carboxy-vinyl copolymers, carboxymethyl hydroxyethylcellulose,cellulose, such as microcrystalline cellulose, combinations ofmicrocrystalline cellulose with sodium carboxymethylcellulose (such asAvicel RC-501, RC-581, RC-591, and CL-611), hydrophobically modifiedhydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl guar,hydroxypropyl methylcellulose (such as Benecel K750 ® or BenecelK1500®), hydroxypropyl cellulose, methyl cellulose, natural gums andtheir derivatives, xanthan gum, guar gum, gum Arabic, partially andfully hydrolyzed polyvinyl alcohols, partially neutralized polyacrylicacid, polyalkylene glycol, polysaccharide gums, polyvinylpyrrolidone andderivatives thereof, starch and its derivatives, vinylpyrrolidone homo-and copolymers, water-soluble cellulose ethers, and the mixturesthereof.

These compositions can be sterilized by conventional sterilizationtechniques. The resulting aqueous solutions may be packaged for use orfiltered under aseptic conditions and lyophilized. The lyophilizedpreparation can be combined with a sterile aqueous solution prior toadministration. The compositions can contain pharmaceutically acceptableauxiliary substances as appropriate to approximate physiologicalconditions, such as tonicity adjusting agents and the like, for example,sodium acetate, sodium lactate, sodium chloride, potassium chloride,calcium chloride, sodium lactate, sorbitan monolaurate, triethanolamineoleate, etc. Pharmaceutical compositions can be selected according totheir physical characteristic, including, but not limited to fluidvolumes, viscosities and other parameters in accordance with theparticular mode of administration selected.

Conjugate

In one aspect, provided herein is a radiopharmaceutical compositioncomprising a conjugate or pharmaceutically acceptable salts or solvatesthereof described herein. The radiopharmaceutical composition canfurther comprise a pharmaceutically acceptable carrier such as anaqueous vehicle. Normal saline can be employed as the pharmaceuticallyacceptable carrier. Other suitable carriers or aqueous vehicles caninclude, e.g., water, buffered water, 0.9% isotonic saline, 0.4% saline,0.3% glycine, and the like, including glycoproteins for enhancedstability, such as albumin, lipoprotein, globulin, etc. In someembodiments, the aqueous vehicle is water for injection. In someembodiments, the aqueous vehicle is 0.9% w/w sodium chloride salinesolution.

The amount of conjugates administered can depend upon the particulartargeting moiety used, the disease state being treated, the therapeuticagent being delivered, and the judgment of the clinician.

The concentration of the conjugates or pharmaceutically acceptable saltsor solvates thereof described herein in the pharmaceutical formulationscan vary. In some embodiments, the conjugate is present in thepharmaceutical composition from about 0.05% to about 1% by weight, about1% to about 2% by weight, about 2% to about 5% by weight, about 5% toabout 10% by weight, about 10% to about 30% by weight, about 30% toabout 50% by weight, about 50% to about 75% by weight, or about 75% toabout 99% by weight.

In some embodiments, the conjugate is present in the pharmaceuticalcomposition in an amount that provides a radioactivity of about 0.5 toabout 1000 μCi/ml. In some embodiments, the conjugate is present in thepharmaceutical composition in an amount that provides a radioactivity ofabout 1 to about 15 μCi/ml, about 2 to about 20 μCi/ml, about 5 to about50 μCi/ml, about 10 to about 100 μCi/ml, about 20 to about 200 μCi/ml,about 50 to about 500 μCi/ml, about 100 to about 250 μCi/ml, about 5 toabout 25 μCi/ml, about 10 to about 30 μCi/ml, or about 5 to about 15μCi/ml. In some embodiments, the conjugate is present in theradiopharmaceutical composition at a concentration equivalent to about15 to 45 μCi/mL. In some embodiments, the conjugate is present in theradiopharmaceutical composition at a concentration equivalent to about10 to 35 μCi/mL. In some embodiments, the conjugate is present in theradiopharmaceutical composition at a concentration equivalent to about10 to 25 μCi/mL. In some embodiments, the conjugate is present in theradiopharmaceutical composition at a concentration equivalent to about12 to 23 μCi/mL. In some embodiments, the conjugate is present in thepharmaceutical composition in an amount that provides a radioactivity ofat most about 5, 10, 15, 50, 75, 100, 200, or 500 μCi/ml. In someembodiments, the conjugate is present in the pharmaceutical compositionin an amount that provides a radioactivity of at most about 15 μCi/ml.In some embodiments, the conjugate is present in the pharmaceuticalcomposition in an amount that provides a radioactivity of about 1 to 15μCi/ml. In some embodiments, the conjugate is present in thepharmaceutical composition in an amount that provides a radioactivity ofat most about 35 μCi/ml. In some embodiments, the conjugate is presentin the pharmaceutical composition in an amount that provides aradioactivity of about 1 to 35 μCi/ml. In some embodiments, theconjugate is present in the pharmaceutical composition in an amount thatprovides a radioactivity of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, or 50 μCi/ml.

A composition described herein can comprise a conjugate, or apharmaceutically acceptable salt or solvate thereof, that comprisesactinium-225. In some embodiments, actinium-225 is present in aherein-described radiopharmaceutical composition that it provides avolumetric radioactivity of about 0.005 to 1000 MBq/mL. In someembodiments, the actinium-225 is present in a herein-describedradiopharmaceutical composition that it provides a volumetricradioactivity of about 0.5 to 20 MBq/mL. In some embodiments, theactinium-225 is present in a herein-described radiopharmaceuticalcomposition that it provides a volumetric radioactivity of about 0.4 to20 MBq/mL. In some embodiments, the actinium-225 is present in aherein-described radiopharmaceutical composition that it provides avolumetric radioactivity of about 0.2 to 5 MBq/mL. In some embodiments,the actinium-225 is present in a herein-described radiopharmaceuticalcomposition that it provides a volumetric radioactivity of about 0.4 to1 MBq/mL. In some embodiments, actinium-225 is present in aherein-described radiopharmaceutical composition that it provides avolumetric radioactivity of about 0.1 to 100 MBq/mL. In someembodiments, actinium-225 is present in a herein-describedradiopharmaceutical composition that it provides a volumetricradioactivity of about 0.1 to 100, about 0.1 to 50, about 0.1 to 25,about 0.1 to 10, about 0.1 to 5, about 1 to 100, about 0.5 to 10, about0.5 to 50, about 10 to 100, about 10 to 50, about 10 to 20, about 1 to10, or about 1 to 20 MBq/mL. In some embodiments, actinium-225 ispresent in a herein-described radiopharmaceutical composition that itprovides a volumetric radioactivity of about 0.1, 0.5, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25or 30 MBq/mL. In some embodiments, actinium-225 is present in aherein-described radiopharmaceutical composition that it provides avolumetric radioactivity of at least about 0.001, 0.01, 0.1, 0.5, 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, or 25 MBq/mL. In some embodiments, actinium-225 is present in aherein-described radiopharmaceutical composition that it provides avolumetric radioactivity of at most about 0.5, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30,40 or 50 MBq/mL. In some embodiments, a composition described herein hasa total DOTA-TATE peptide concentration of ≤11.5 μg/mL (including e.g.,unlabeled DOTATATE, ²²⁵Ac-DOTATATE, and metal-DOTATATE species). In someembodiments, a composition described herein has a total DOTA-TATEpeptide concentration of at most about 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20 or 50 μg/mL. In some embodiments, acomposition described herein has a total DOTA-TATE peptide concentrationof at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, or 20 μg/mL.

The composition described herein can comprise a conjugate, or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable excipient or carrier. The conjugate asdescribed can be substantially pure, in that it contains less than about10%, less than about 5%, or less than about 1%, or less than about 0.1%by weight, of other organic small molecules, such as unreactedintermediates or synthesis by-products that are created, for example, inone or more of the steps of a synthesis method. The conjugate can be²²⁵Ac-DOTA-TATE or ²²⁵Ac-DOTA-TOC. The conjugate can be ²²⁵Ac-DOTA-TATE.The conjugate can be ²²⁵Ac-DOTA-TOC.

²²⁵Ac-DOTA-TATE can be illustrated as having the following structure:

The IUPAC Name for ²²⁵Ac-DOTA-TATE is:(2,2′,2″-(10-(2-(((R)-1-(((4R,7S,10S,13R,16S,19R)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-4-(((1S,2R)-1-carboxy-2-hydroxypropyl)carbamoyl)-16-(4-hydroxybenzyl)-7-((R)-1-hydroxyethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosan-19-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate;actinium-225(3+)).

In some embodiments, provided herein is a pharmaceutical compositioncomprising a conjugate that is

and one or more stabilizing agents.

In some embodiments, provided herein is a pharmaceutical compositioncomprising a conjugate that has a structure of

and one or more stabilizing agents. In some embodiments, provided hereinis a pharmaceutical composition comprising a conjugate that has astructure of

and one or more stabilizing agents. It is understood that the chelationbetween ²²⁵Ac and the metal chelator is not shown in the above twostructures. In some embodiments, for example in acidic aqueousconditions, the radionuclide actinium-225 exists in a salt form, e.g.,as ²²⁵Ac³⁺. In some embodiments, the conjugate is in a salt form. Insome embodiments, the conjugate is an acetate salt. In some embodiments,provided herein is a pharmaceutical composition comprising a conjugatethat is

and one or more stabilizing agents. In some embodiments, provided hereinis a pharmaceutical composition comprising a conjugate that is

and one or more stabilizing agents. It is understood that the chelationbetween ²²⁵Ac and the metal chelator is not shown in the above twostructures. In some embodiments, for example in acidic aqueousconditions, the radionuclide actinium-225 exists in a salt form, e.g.,as ²²⁵Ac³⁺. In some embodiments, the conjugate is in a salt form. Insome embodiments, the conjugate is an acetate salt. A person of ordinaryskill would appreciate that the dissociation of an acid can depend onthe pH value of the environment and its pK value. Accordingly, in someembodiments, a conjugate described herein can exist in a completelyionized, partially ionized or non-ionized form.Targeting Ligand

In one aspect, provided herein is a radiopharmaceutical compositioncomprising a conjugate or pharmaceutically acceptable salts or solvatesthereof. In some embodiments, the conjugate described herein comprises atargeting ligand and a metal chelator.

The targeting ligand described herein can bind to one or more targetwithin a subject's system or an in vitro system. The targeting ligandcan target a protein, a receptor on a cell, or other chemical moietythat can perform signaling functions within the subject's system. Thetargeting ligand can bind to a receptor on the surface of a cell withinthe subject's system. In some embodiments, the targeting ligand binds toa somatostatin receptor (SSR). An SSR can be a mammalian SSR. Amammalian SSR can be a human SSR. A human SSR can comprise somatostatinreceptor type 1 (SSTR1), somatostatin receptor type 2 (SSTR2),somatostatin receptor type 3 (SSTR3), somatostatin receptor type 4(SSTR4), and/or somatostatin receptor type 5 (SSTR5). An SSR can be ahuman somatostatin receptor type 2 (SSTR2). In some embodiments, thetargeting ligand binds to a human somatostatin receptor type 2 (SSTR2).The targeting ligand can comprise a peptide and/or a small moleculecompound. The targeting ligand can comprise an agonist of the SSR. Thetargeting ligand can comprise an antagonist of the SSR. The agonist ofthe SSR can comprise a partial agonist of the SSR. The agonist of theSSR can comprise a full agonist of the SSR. The agonist of the SSR cancomprise an inverse agonist of the SSR. The antagonist of the SSR cancomprise a competitive antagonist of the SSR. The targeting ligand cancomprise an allosteric modulator of the SSR. The allosteric modulator ofthe SSR can be an allosteric agonist of SSR. The allosteric modulator ofthe SSR can be an allosteric antagonist of SSR.

The targeting ligand described herein can comprise one or more peptides,which can be the same or different. The peptide can be linear or cyclic.The peptide can be monocyclic. The peptide can comprise a bindingpeptide. The binding peptide can bind to one or more target within asubject's system or an in vitro system. The binding peptide can bind toa somatostatin receptor (SSR). The binding peptide can bind to asomatostatin receptor type 1 (SSTR1), somatostatin receptor type 2(SSTR2), somatostatin receptor type 3 (SSTR3), somatostatin receptortype 4 (SSTR4), and/or somatostatin receptor type 5 (SSTR5). The bindingpeptide can bind to a somatostatin receptor type 2 (SSTR2). The bindingpeptide can bind to a human somatostatin receptor type 2 (SSTR2).

The peptide can comprise any suitable number of amino acid residues. Thepeptide can comprise from 4 to 50, 5 to 40, 6 to 30, 7 to 20, or 8 to 10amino acid residues. The peptide can comprise from 6 to 14 amino acidresidues. The peptide can comprise from 6 to 10 amino acid residues. Thepeptide can comprise from 7 to 9 amino acid residues. The peptide cancomprise 8 to 9 amino acid residues. The peptide can comprise 14 aminoacid residues. The peptide can comprise 13 amino acid residues. Thepeptide can comprise 12 amino acid residues. The peptide can comprise 11amino acid residues. The peptide can comprise 10 amino acid residues.The peptide can comprise 9 amino acid residues. The peptide can comprise8 amino acid residues. The peptide can comprise 7 amino acid residues.The peptide can comprise 6 amino acid residues. The peptide can consistof 10 amino acid residues. The peptide can consist of 14 amino acidresidues. The peptide can consist of 13 amino acid residues. The peptidecan consist of 12 amino acid residues. The peptide can consist of 11amino acid residues. The peptide can consist of 10 amino acid residues.The peptide can consist of 9 amino acid residues. The peptide canconsist of 8 amino acid residues. The peptide can consist of 7 aminoacid residues. The peptide can consist of 6 amino acid residues. Theconjugate can comprise a monocyclic peptide of 6, 7, 8, 9, 10, 11, 12,13, or 14 amino acid residues. The amino acid residues described hereincan be modified to remove or add one or more functional groups.

A targeting ligand described herein can be a cyclized peptide.Cyclization can be achieved via a single disulfide bond or via a peptidebond, alkyl bond, alkenyl bond, ester bond, thioester bond, ether bond,thioether bond, phosphate ether bond, azo bond, C—S—C bond, C—N—C bond,C═N—C bond, C═N—O bond, amide bond, lactam bridge, carbamoyl bond, ureabond, thiourea bond, amine bond, thioamide bond, or the like, but notlimited to them. The peptide can comprise a cyclic peptide that iscyclized by a peptide bond. A cyclization of a peptide can stabilize thepeptide structure and thereby enhance affinity for a target. Thecyclization can occur between the N- and C-terminus, or it can occurbetween a terminal amino acid and a non-terminal amino acid. Thecyclization can occur between two non-terminal amino acids. The peptidecan be cyclized via one or more cysteines. The peptide can comprise acysteine at the C-terminus. The peptide can comprise a cysteine at theN-terminus. The cyclization can occur via a disulfide bond betweencysteines or between cysteine and another thiol group-bearing residue.

Exemplary targeting ligands include BMS-753493, Somatostatins orsomatotropin release inhibiting factor (SRIF), SRIF-14, SRIF-28,Octreotide, Octreotate, Lanreotide, Pasireotide, JR-11, L-779,976,BIM-23120, Satoreotide, depreotide, 18F-KYNDRLPLYISNP (SEQ ID NO: 103),CaIX-P1, and FAP-2286. The targeting ligand can comprise octreotate,octreotide, D-Phe1-cyclo(Cys2-Tyr3-D-Trp4-Lys5-Thr6-Cys7)Thr8 (SEQ IDNO: 97) (tyr3-octreotate or TATE),D-Phe1-cyclo(Cys2-Tyr3-D-Trp4-Lys5-Thr6-Cys7)Thr(ol)8 (SEQ ID NO: 98)(Phe1-Tyr3octreotide, edotreotide, or TOC),D-Phe1-cyclo(Cys2-Phe3-D-Trp4-Lys5-Thr6-Cys7)Thr(ol)8 (SEQ ID NO: 99)(OC), D-Phe1-cyclo(Cys2-1-Nal-D-Trp4-Lys5-Thr6-Cys7)Thr(ol)8 (SEQ ID NO:100) (NOC),p-Cl-Phe-cyclo(D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys)D-Tyr-NH₂) (SEQ IDNO: 101) (JR11), orp-Cl-Phe-cyclo(D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys)-D-Tyr-NH₂ (SEQ ID NO:102) (LM3). The targeting ligand can be tyr3-octreotate, edotreotide,octreotate, or octreotide. The targeting ligand can be tyr3-octreotate.

The binding peptide can comprise an amino acid sequence with at least70% identity to a sequence selected from SEQ IDs 1 to 96. The bindingpeptide can comprise an amino acid sequence with at least 75% identityto a sequence selected from SEQ IDs 1 to 96. The binding peptide cancomprise an amino acid sequence with at least 80% identity to a sequenceselected from SEQ IDs 1 to 96. The binding peptide can comprise an aminoacid sequence with at least 85% identity to a sequence selected from SEQIDs 1 to 96. The binding peptide can comprise an amino acid sequencewith at least 85% identity to a sequence selected from SEQ IDs 1 to 96.The binding peptide can comprise an amino acid sequence with at least90% identity to a sequence selected from SEQ IDs 1 to 96. The bindingpeptide can comprise an amino acid sequence with at least 95% identityto a sequence selected from SEQ IDs 1 to 96. The binding peptide cancomprise an amino acid sequence with at least 98% identity to a sequenceselected from SEQ IDs 1 to 96. The binding peptide can comprise an aminoacid sequence with at least 99% identity to a sequence selected from SEQIDs 1 to 96. The binding peptide can comprise an amino acid sequence anamino acid sequence selected from SEQ IDs 1 to 96, as listed in Table 4.

TABLE 4 start at 31 Sequence ID List SEQ ID Sequences 1H-^(D)Phe-c[Cys-Tyr-^(D)Trp-Lys-Val-Cys]-Trp-OH 2H-^(D)3Pal-c[Cys-Tyr-^(D)Trp-Lys-Val-Cys]-Thr-OH 3H-^(D)Phe-c[Cys-Phe-^(D)Trp-Lys-Thr-Cys]-Thr[oll 4H-Nal-c[^(D)Cys-3Pal-^(D)Trp-Lys-Ala-Cys]Na!OH 5H-Nal-c[^(D)Cys-3Pal-^(D)Trp-Lys-Gly-Cys]-Nal-OH 6H-Nal-c[^(D)Cys-3Pal-^(D)Trp-Lys-Ile-Cys]-Nal-OH 7H-Nal-c[^(D)Cys-3Pal-^(D)Trp-Lys-Leu-Cys]-Nal-OH 8H-Nal-c[^(D)Cys-3Pal-^(D)Trp-Lys-Val-Cys]-Nal-OH 9H-c[Cys-Lys-Phe-Phe-^(D)Trp-Amp-Thr-Phe-Thr-Ser-Cys]-OH 10H-Ser-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-Arg-Glu-Arg-Lys-Ala-Gly-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys]-OH 11H-c[Cys-Phe-Phe-Trp-Lys-Thr-Phe-Cys]-OH(OLT-8) 12H-c[Cys-Phe-Phe-^(D)Trp-Lys-Thr-Phe-Cys]-OH(O^(D)T-8) 13H-c[Cys-^(L)Agl(N^(β)Me,benzoyl)-Phe-^(D)Trp-Lys-Thr-Phe-Cys]-OH 14H-c[Cys-^(D)Agl(NβMe,benzoyl)-Phe-^(D)Trp-Lys-Thr-Phe-Cys]-OH 15H-c[Cys-Phe-^(L)Agl(N^(β)Me,benzoyl)-Trp-Lys-Thr-Phe-Cys]-OH 16H-c[Cys-Phe-^(D)Agl(N^(β)Me,benzoyl)-Trp-Lys-Thr-Phe-Cys]-OH 17H-c[Cys-Phe-LAgl(N^(β)Me,benzoyl)-^(D)Trp-Lys-Thr-Phe-Cys]-OH 18H-c[Cys-Phe-^(D)Agl(N^(β)Me,benzoyl)-^(D)Trp-Lys-Thr-Phe-Cys]-OH 19H-c[^(D)Cys-Phe-^(L)Agl(N^(β)Me,benzoyl)-^(D)Trp-Lys-Thr-Phe-Cy s]-OH 20H-c[^(D)Cys-Phe-^(D)Agl(N^(β)Me,benzoyl)-^(D)Trp-Lys-Thr-Phe-Cys]-OH 21H-Tyr-c[Cys-Phe-^(L)Agl(N^(β)Me,benzoyl)-Trp-Lys-Thr-Phe-Cys]-OH 22H-Tyr-c[Cys-Phe-^(D)Agl(N^(β)Me,benzoyl)-Trp-Lys-Thr-Phe-Cys]-OH 23H-Tyr-c[Cys-Phe-^(L)Agl(N^(β)Me,benzoyl)-^(D)Trp-Lys-Thr-Phe-Cys]-OH 24H-Tyr-c[Cys-Phe-^(D)Agl(N^(β)Me,benzoyl)-^(D)Trp-Lys-Thr-Phe-Cys]-OH 25H-c[Cys-Phe-Phe-^(D)Trp-^(L)Agl(^(β)Ala)-Thr-Phe-Cys]-OH 26H-c[Cys-Phe-Phe-^(D)Trp-^(D)Agl(^(β)Ala)-Thr-Phe-Cys]-OH 27H-c[Cys-Phe-Phe-^(D)Trp-^(L)Agl(N^(β)Me, ^(β)Ala)-Thr-Phe-Cys]-OH 28H-c[Cys-Phe-Phe-^(D)Trp-^(D)Agl(N^(β)Me, ^(β)Ala)-Thr-Phe-Cys]-OH 29H-c[Cys-Phe-Phe-^(D)Trp-Lys-^(L)Agl-(N^(β)Me,HO-Ac)-Phe-Cys]-OH 30H-c[Cys-Phe-Phe-^(D)Trp-Lys-^(D)Agl-(N^(β)Me,HO-Ac)-Phe-Cys]-OH 31H-c[Cys-Phe-Phe-^(D)Trp-Lys-Thr-^(L)Agl(N^(β)Me,benzoyl)-Cys]-OH 32H-c[Cys-Phe-Phe-^(D)Trp-Lys-Thr-^(L)Agl(N^(β)Me,benzoyl)-Cys]-OH 33H-c[Cys-Phe-Phe-^(D)Trp-Lys-Thr-Tyr-Cys]-OH 34H-c[Cys-Phe-Phe-Trp-Lys-Thr-Tyr-Cys]-OH 35H-c[Cys-Phe-Xle-Trp-Lys-Thr-Phe-Cys]-OH 36H-c[Cys-Phe-Tyr-^(D)Trp-Lys-Thr-Phe-Cys]-OH 37H-c[Cys-Phe-Tyr-Trp-Lys-Thr-Phe-Cys]-OH 38H-Tyr-c[Cys-Phe-Ala-^(D)Trp-Lys-Thr-Phe-Cys]-OH 39H-Tyr-c[Cys-Phe-Ala-Trp-Lys-Thr-Phe-Cys]-OH 40H-Tyr-c[Cys-Phe-Phe-Trp-Lys-Thr-Phe-Cys]-OH 41H-Tyr-c[Cys-Phe-Xle-Trp-Lys-Thr-Phe-Cys]-OH 42H-Ala-Gly-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser- Cys]-OH 43H-c[Cys-Phe-Ala-^(D)Trp-Lys-Thr-Ala-Cys]-OH 44H-c[Cys-Phe-Ala-^(D)Trp-Lys-Thr-Phe-Cys]-OH 45H-c[Cys-Phe-Phe-^(D)Trp-Lys-Thr-Phe-Cys]-OH 46H-c[Cys-Phe-Phe-Trp-Lys-Thr-Phe-Cys]-OH 47H-N(Me)-c[Cys-Lys-Phe-Phe-^(D)Nal-Amp-Thr-Phe-Thr-Ser-Cys]-OH 48H-N(Me)-c[Cys-Lys-Phe-Phe-^(D)Trp-Amp-Thr-Phe-Thr-Ser-Cys]-OH 49H-N(Me)-c[Cys-Lys-Phe-Phe-^(D)Trp-Amp(NMe)-Thr-Phe-Thr-Ser- Cys]-OH 50H-c[Cys-Lys-Phe-Phe-^(D)Nal-Amp-Thr-Phe-Thr-Ser-Cys]-OH 51H-c[Cys-Lys-Phe-Phe-^(D)Trp-Lys-Thr-Tyr-Thr-Ser-Cys]-OH 52H-c[Cys-Lys-Phe-Phe-Trp-3Pal-Thr-Tyr-Thr-Ser-Cys]-OH 53H-c[Cys-Phe-^(D)Trp-Lys-Thr-Phe-Cys]-OH 54H-c[Cys-Phe-Phe-^(D)Trp-Lys-Phe-Cys]-OH 55H-c[Cys-Phe-Phe-^(D)Trp-Lys-Thr-Cys]-OH 56H-c[Cys-Phe-Phe-^(D)Trp-Lys-Thr-Phe-Thr-Cys]-OH 57H-c[Cys-Phe-Phe-^(D)Trp-Lys-Thr-Phe-Thr-Cys]-OH 58H-c[Cys-Lys-Phe-Phe-^(D)Trp-3Pal-Thr-Phe-Cys]-OH 59H-c[Cys-Lys-Phe-Phe-^(D)Trp-Lys-Thr-Phe-Cys]-OH 60H-c[Cys-Asn-Phe-Phe-^(D)Trp-Lys-Thr-Phe-Cys]-OH 61H-c[Cys-Asn-Phe-Phe-^(D)Trp-Lys-Thr-Phe-Thr-Cys]-OH 62H-Tyr-c[Cys-Phe-^(D)Trp-Lys-Thr-Phe-Cys]-OH 63H-Tyr-c[Cys-Lys-Phe-^(D)Trp-3Pal-Thr-Phe-Thr-Cys]-OH 64H-Tyr-c[Cys-Lys-Glu2-Phe-^(D)Trp-3Pal-Thr-Phe-Lys2-Ser-Cys]-OH 65H-Tyr-c[Cys-Lys-Phe-Glu2-Phe-^(D)Trp-3Pal-Thr-Phe-Lys2-Ser- Cys]-OH 66H-c[Cys-Phe-4Aph-Trp-Lys-Thr-Phe-Cys]-OH 67H-c[Cys-Phe-4Aph-^(D)Trp-Lys-Thr-Phe-Cys]-OH 68H-N(Cbm)-c[Cys-Phe-4Aph-Trp-Lys-Thr-Phe-Cys]-OH 69H-N(Cbm)-c[Cys-Phe-4Aph-^(D)-Trp-Lys-Thr-Phe-Cys]-OH 70H-c[Cys-Phe-4Aph-2Nal-Lys-Thr-Phe-Cys]-OH 71H-Tyr-c[Cys-Phe-4Aph-Trp-Lys-Thr-Phe-Cys]-OH 72H-Tyr-c[Cys-Phe-4Aph-^(D)-Trp-Lys-Thr-Phe-Cys]-OH 73H-N(Cbm)-Tyr-c[Cys-Phe-4Aph-Trp-Lys-Thr-Phe-Cys]-OH 74H-c[Cys-Phe-4Aph-Trp-Lys-Thr-Tyr-Cys]-OH 75H-N(Cbm)-c[Cys-Phe-4Aph-Trp-Lys-Thr-Tyr-Cys]-OH 76H-c[Cys-Phe-Ala-Trp-Lys-Thr-Phe-Cys]-OH 77H-Tyr-c[Cys-Phe-Ala-Trp-Lys-Thr-Phe-Cys]-OH 78H-Tyr-c[Cys-Phe-Ala-^(D)-Trp-Lys-Thr-Phe-Cys]-OH 79H-Tyr-c[Cys-Phe-4Amp-Trp-Lys-Thr-Phe-Cys]-OH 80H-c[^(D)Cys-Phe-Tyr-threo-(2R,3S)CI^(β)Me-2Nal-Lys-Thr-Phe-Cys]-OH 81H-c[Cys-Phe-Tyr-threo-(2R,3S)C^(β)Me-2Nal-Lys-Thr-Phe-Cys]-OH 82H-N(Cbm)-c[Cys-Phe-4Aph-^(D)-Trp-Lys-Thr-Tyr-Cys]-OH 83H-c[Cys-Phe-Val-^(D)Trp-Lys-Thr-Phe-Cys]-OH 84H-c[Cys-Phe-Ala-Trp-Lys-Thr-Ala-Cys]-OH 85H-c[Cys-Phe-Ala-^(D)Trp-Lys-Thr-Ala-Cys]-OH 86H-c[Cys-Phe-Ala-Trp-Lys-Thr-Phe-Cys]-OH 87H-GABA-c[Cys-Phe-Ala-Trp-Lys-Thr-Phe-Cys]-OH 88H-c[Cys-Phe-Ala-Trp-Lys-Thr-Val-Cys]-OH 89H-c[Cys-Phe-Val-Trp-Lys-Thr-Val-Cys]-OH 90H-c[Cys-Phe-Ala-Trp-Lys-Thr-Gly-Cys]-OH 91H-Phe-c[Cys-Phe-Ala-Trp-Lys-Thr-Phe-Cys]-OH 92H-N(Cbm)-Tyr-c[Cys-Phe-Ala-Trp-Lys-Thr-Phe-Cys]-OH 93H-N(Cbm)-Tyr-c[Cys-Phe-Amp-Trp-Lys-Thr-Phe-Cys]-OH 94H-Tyr-c[Cys-Phe-4Iamp-Trp-Lys-Thr-Phe-Cys]-OH 95H-c[^(D)Cys-Phe-Tyr-threo-(2S,3R)C^(β)Me-2Nal-Lys-Thr-Phe-Cys]-OH 96H-c[Cys-Phe-Tyr-threo-(2S,3R)C^(β)Me-2Nal-Lys-Thr-Phe-Cys]-OH

Exemplary abbreviations and modifications in Table 4 are illustrated inFIG. 18A and FIG. 18B.

The targeting ligands can further comprise small molecule compounds.Such small molecule compounds can comprise L-797,591, L-779,976,L-796,778, L-803,087, or L-817,818, the structures of which areillustrated in FIG. 2A

The targeting ligand can have a binding affinity to a human SSR that isnot more than about 1 mM, by half maximal inhibitory concentration(IC50). The targeting ligand can have a binding affinity to a human SSRthat is not more than about 1000 nM, by half maximal inhibitoryconcentration (IC50). The targeting ligand can have a binding affinityto a human SSR that is not more than about 500 nM, by half maximalinhibitory concentration (IC50). The targeting ligand can have a bindingaffinity to a human SSR that is not more than about 250 nM, by halfmaximal inhibitory concentration (IC50). The targeting ligand can have abinding affinity to a human SSR that is not more than about 200 nM, byhalf maximal inhibitory concentration (IC50). The targeting ligand canhave a binding affinity to a human SSR that is not more than about 150nM, by half maximal inhibitory concentration (IC50). The targetingligand can have a binding affinity to a human SSR that is not more thanabout 100 nM, by half maximal inhibitory concentration (IC50). Thetargeting ligand can have a binding affinity to a human SSR that is notmore than about 75 nM, by half maximal inhibitory concentration (IC50).The targeting ligand can have a binding affinity to a human SSR that isnot more than about 50 nM, by half maximal inhibitory concentration(IC50). The targeting ligand can have a binding affinity to a human SSRthat is not more than about 25 nM, by half maximal inhibitoryconcentration (IC50). The targeting ligand can have a binding affinityto a human SSR that is not more than about 10 nM, by half maximalinhibitory concentration (IC50). The targeting ligand can have a bindingaffinity to a human SSR that is not more than about 5 nM, by halfmaximal inhibitory concentration (IC₅₀). The targeting ligand can have abinding affinity to a human SSR that is not more than about 2 nM, byhalf maximal inhibitory concentration (IC₅₀). The targeting ligand cancomprise a monocyclic peptide or peptide mimics or derivatives thereof.

Radionuclide

In one aspect, described herein are conjugates that comprise aradionuclide. Exemplary radionuclides include, but are not limited to,astatine-211, astatine-217, actinium-225, americium-243, radium-223,lead-212, lead-203, copper-64, copper-67, copper-60, copper-61,copper-62, bismuth-212, bismuth-213, gallium-68, gallium-67,dysprosium-154, gadolinium-148, gadolinium-153, samarium-146,samarium-147, samarium-153, terbium-149, thorium-227, thorium-229,iron-59, yttrium-86, indium-111, holmium-166, technetium-94,technetium-99^(m), yttrium-90, lutetium-177, terbium-161, rhenium-186,rhenium-188, cobalt-55, scandium-43, scandium-44, scandium-47,dysprosium-166, fluorine-18, or iodine-131.

Generally, the type of radionuclide used in a therapeuticradiopharmaceutical can be tailored to the specific type of cancer, thetype of targeting moiety, etc. Radionuclides that undergo α-decayproduce particles composed of two neutrons and two protons, andradionuclides that undergo β-decay emit energetic electrons from theirnuclei. Some radionuclides can also emit Auger. In some embodiments, theconjugate comprises an alpha particle-emitting radionuclide. Alpharadiation can cause direct, irreparable double-strand DNA breakscompared with gamma and beta radiation, which can cause single-strandedbreaks via indirect DNA damage. The range of these particles in tissueand the half-life of the radionuclide can also be considered indesigning the radiopharmaceutical conjugate. Tables 5A and 5B belowillustrate some properties of exemplary radionuclides.

TABLE 5A Exemplary radionuclides Nuclide Emission Half-life (days)Actinium-225 (Ac-225) α about 9.92 Lutetium (Lu-177) β about 6.646Radium-223 α about 11.4 Radium-224 α About 3.63 Astatine-211 α about 0.3Yttrium-90 β about 2.7 Iodine-131 β about 8 Samarium-153 β about 1.9Lead-212 β about 0.4 Bismuth-212 α about 0.04 Thorium-227 α about 18.7Terbium-149 α about 0.17

TABLE 5B Exemplary radionuclides Nuclide Half-life Lutetium-177 (Lu-177)about 6.646 days Indium-111 (In-111) about 2.8 days Gallium-68 (Ga-68)about 68 minutes Copper-64 (Cu-64) about 12.7 hours Zirconium-89 (Zr-89)about 78.4 hours

In some embodiments, a conjugate described herein comprises one or moreindependent radionuclides. In some embodiments, the conjugate comprisestwo radionuclides. In some embodiments, each of the one or moreradionuclides is bound to a metal chelator of the conjugate. In someembodiments, two radionuclides of a conjugate are bound to the samemetal chelator. In some embodiments, two radionuclides of a conjugateare bound to two independent metal chelators. In some embodiments, eachof the one or more radionuclides is an alpha particle-emittingradionuclide.

In some embodiments, a conjugate described herein comprises an alphaparticle-emitting radionuclide. In some embodiments, the alphaparticle-emitting radionuclide is actinium-225 (²²⁵Ac), astatine-211(²¹¹At) radium-223 (²²³Ra), radium-224 (²²⁴Ra), bismuth-213 (²¹³Bi),Terbium-149 (¹⁴⁹TB), or thorium-227 (²²⁷Th). In some embodiments, thealpha particle-emitting radionuclide is ²²⁵AC. In some embodiments, thealpha particle-emitting radionuclide is ²¹³Bi. In some embodiments, thealpha particle-emitting radionuclide is ²¹²Bi. In some embodiments, thealpha particle-emitting radionuclide is ²¹²Pb. In some embodiments, thealpha particle-emitting radionuclide is ²²⁴Ra. In some embodiments, thealpha particle-emitting radionuclide is ²²³Ra. In some embodiments, thealpha particle-emitting radionuclide is ²²⁷Th. In some embodiments, thealpha particle-emitting radionuclide is ²¹¹At. In some embodiments, thealpha particle-emitting radionuclide is ¹⁴⁹Tb. In some embodiments, theradionuclide is Zirconium-89 (⁸⁹Zr). In some embodiments, a conjugatedescribed herein comprises a radionuclide selected from ⁶⁷Cu, ⁶⁴Cu,⁸⁹Zr, ⁹⁰Y, ¹⁰⁹pd, ¹¹¹Ag, ¹⁴⁹Pm, ¹⁵³Sm, ¹⁶⁶Ho, ^(99m)Tc, ⁶⁷Ga, ⁶⁸Ga,¹¹¹In, ⁹⁰Y, ¹⁷⁷Lu, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁹⁷Au, ¹⁹⁸Au, ¹⁹⁹Au, ¹⁰⁵Rh, ¹⁶⁵Ho,¹⁶¹Tb, ¹⁴⁹Pm, ⁴⁴Sc, ⁴⁷Sc, ⁷⁰As, ⁷¹As, ⁷²As, ⁷³As, ⁷⁴As, ⁷⁶As, ⁷⁷As,²¹²pb, ²¹²Bi, ²¹³Bi, ²²⁵Ac, ^(117m)Sn, ⁶⁷Ga, ²⁰¹Tl, ¹²³I, ¹³¹I, ¹⁶⁰Gd,¹⁴⁸Nd, ⁸⁹Sr, and ²¹¹At. In some embodiments, the radionuclide is ²²⁵Ac.In some embodiments, the radionuclide is a decay daughter of ²²⁵Ac suchas ²²¹Fr, ²¹⁷At, ²¹³Bi, ²¹³Po, ²⁰⁹Tl, ²⁰⁹, or ²⁰⁹Bi. In someembodiments, the conjugate comprises two ²²⁵Ac radionuclides. In someembodiments, the radionuclide is ¹⁷⁷Lu. In some embodiments, theconjugate comprises two ¹⁷⁷Lu radionuclides.

In some embodiments, the conjugate comprises an alpha particle-emittingradionuclide bound to the metal chelator. In some embodiments, the alphaparticle-emitting radionuclide is actinium-225, astatine-211,thorium-227, or radium-223. In some embodiments, the alphaparticle-emitting radionuclide is actinium-225.

In some embodiments, the conjugate comprises a beta particle-emittingradionuclide bound to the metal chelator. In some embodiments, the betaparticle emitting radionuclide is zircronium-89, yttrium-90, iodine-131,samarium-153, lutetium-177, or lead-212.

In some embodiments, the conjugate comprises a gamma particle emittingradionuclide. In some embodiments, the gamma particle emittingradionuclide is indium-111.

In some embodiments, conjugates described herein do not contain anyradionuclide, i.e., a cold conjugate. For example, in some cases, aradionuclide can be replaced with a surrogate (e.g. 225Ac replaced withlanthanum) for testing and experimental purposes.

Metal Chelator

In one aspect, described herein are conjugates that comprise a metalchelator that is configured to bind with a radionuclide. The metalchelator can refer to a moiety of the conjugate that is configured tobind with a radionuclide. In some embodiments, a conjugate describedherein comprises two or more independent metal chelators, e.g., 2, 3, 4,5, or more metal chelators. In some embodiments, a conjugate describedherein comprises two metal chelators, which can be the same ordifferent. The metal chelator can be attached to the linker or thetargeting ligand through any suitable group/atom of the chelator.

In some embodiments, the metal chelator is capable of binding aradioactive atom. The binding can be direct, e.g., the metal chelatorcan make hydrogen bonds or electrostatic interactions with theradioactive atom. The binding can also be indirect, e.g., the metalchelator binds to a molecule that comprises a radioactive atom. In someembodiments, the metal chelator comprises, or is, a macrocycle. In someembodiments, the metal chelator comprises, or is, DOTA or NOTA. In someembodiments, the metal chelator comprises a macrocycle, e.g., amacrocycle comprising an O and/or a N, DOTA, NOTA, one or more amines,one or more ethers, one or more carboxylic acids, EDTA, DTPA, TETA,DO3A, PCTA, or desferrioxamine.

In some embodiments, the metal chelator comprises a plurality of amines.In some embodiments, the metal chelator includes 4 or more N, 4 or morecarboxylic acid groups, or a combination thereof. In some embodiments,the metal chelator does not comprise S. In some embodiments, the metalchelator comprises a ring. In some embodiments, the ring comprises an Oand/or an N. In some embodiments, the metal chelator is a ring thatincludes 3 or more N, 3 or more carboxylic acid groups, or a combinationthereof. In some embodiments, the metal chelator is poly poly dentate.

In some embodiments, a metal chelator described herein comprises acyclic chelating agent. Exemplary cyclic chelating agents include, butare not limited to, AAZTA, BAT, BAT-TM, Crown, Cyclen, DO2A, CB-DO2A,DO3A, H3HP-DO3A, Oxo-DO3A, p-NH₂-Bn-Oxo-DO3A, DOTA, DOTA-3py, DOTA-PA,DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-1py, p-SCN-Bn-DOTA, CHX-A″-EDTA,MeO-DOTA-NCS EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA,DOTAM, DOTP, CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, NOTA,NOTP, HEHA, HEHA-NCS, p-SCN-Bn-HEHA, DTPA, CHX-A″-DTPA,p-NH₂-Bn-CHX-A″-DTPA, p-SCN-DTPA, p-SCN-Bz-Mx-DTPA, 1B4M-DTPA,p-SCN-Bn1B-DTPA, p-SCN-Bn-1B4M-DTPA, p-SCN-Bn-CHX-A″-DTPA, PEPA,p-SCN-Bn-PEPA, TETPA, DOTPA, DOTMP, DOTPM,t-Bu-calix[4]arene-tetracarboxylic acid, macropa, macropa-NCS, macropid,H₃L¹, H₃L⁴, H₂azapa, H₅decapa, bispa², H₄pypa, H₄octapa, H₄CHXoctapa,p-SCN-Bn-H₄octapa, p-SCN-Bn-H₄octapa, TTHA, p-NO₂-Bn-neunpa, H₄octox,H₂macropa, H₂bispa², H₄phospa, H₆phospa, p-SCN-Bn-H₆phospa, TETA,p-NO₂-Bn-TETA, TRAP, TPA, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA,DMPS, DHLA, lipoic acid, TGA, BAL, Bis-thioseminarabazones, p-SCN-NOTA,nNOTA, NODAGA, CB-TE1A1P, 3P-C-NETA-NCS, 3p-C-DEPA, 3P-C-DEPA-NCS, TCMC,PCTA, NODIA-Me, TACN, pycup1A1B, pycup2A, THP, DEDPA, H₂DEDPA,p-SCN-Bn-H₂DEDPA, p-SCN-Bn-TCMC, motexafin, NTA, NOC, 3p-C-NETA,p-NH₂-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM,CP256, C-NE3TA, C-NE3TA-NCS, NODASA, NETA-monoamide, C-NETA, NOPO, BPCA,p-SCN-Bn-DFO, DFO-ChX-Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD,BAPEN, TACHPYR, NEC-SP, L^(PY), L1, L2, L3, and EuK-106.

In some embodiments, the metal chelator is DO3A. In some embodiments,the metal chelator is PEPA. In some embodiments, the metal chelator isEDTA. In some embodiments, the metal chelator is CHX-A″-DTPA. In someembodiments, the metal chelator is HEHA. In some embodiments, the metalchelator is DOTMP. In some embodiments, the metal chelator ist-Bu-calix[4]arene-tetracarboxylic acid. In some embodiments, the metalchelator is macropa. In some embodiments, the metal chelator ismacropa-NCS. In some embodiments, the metal chelator is H⁴py4pa. In someembodiments, the metal chelator is H₄octapa. In some embodiments, themetal chelator is H4CHXoctapa. In some embodiments, the metal chelatoris DOTP. In some embodiments, the metal chelator is crown.

In some embodiments, the metal chelator is DOTA. In some embodiments,the metal chelator is a chiral derivative of DOTA. Exemplary chiral DOTAchelators are described in Dai et al., Nature Communications (2018)9:857. In some embodiments, the metal chelator is2,2′,2″,2′″-((2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraaceticacid. In some embodiments, the metal chelator has a structure of

In some embodiments, the metal chelator is2,2′,2″,2′″-((2S,5S,8S,11S)-2,5,8,11-tetraethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraaceticacid. In some embodiments, the metal chelator has a structure of

In some embodiments, the conjugate comprises DOTA. In some embodiments,the conjugate comprises a DOTA derivative such as p-SCN-Bn-DOTA andMeO-DOTA-NCS. In some embodiments, the conjugate comprises twoindependent metal chelators, and at least one or both are DOTA. Thestructures of some exemplary metal chelators are illustrated in FIGS.3-17 (without showing the attachment points). Exemplary metal chelatorsare further described in WO2012/174136; US20130183235A1;US20120219495A1; Ramogidaand et al., EJNMMI radiopharm. chem. 4, 21(2019); Thiele et al., Cancer Biotherapy and Radiopharmaceuticals 2018;Li et al., Bioconjugate Chem. 2019, 30, 5, 1539-1553; and Baranyai etal., Eur. J. Inorg. Chem. 36-56 (2020), each of which is incorporated byreference in its entirety.

Linker

Chemical scaffold, covalently joining pharmacophore and metal-chelatorin a targeted radiopharmaceutical, can be referred to as a linker.Incorporating a well-designed inker to a drug molecule can further boostaffinity towards its biological target, accelerate internalization intothe targeted tissues, and optimize the pharmacokinetic properties.Diverse chemical moieties can be used to construct the linkers. Bychanging their physio-chemical characters, the desired in vivocharacters (i.e. absorption, distribution, metabolism, and excretion ofthe drug molecules) can be achieved. In some embodiments,physio-chemical characters of the conjugates can be adjusted by thelinkers, for example, when it is difficult to change pharmacophore andmetal-chelating portions without sacrificing the biological affinity ormetal-binding ability. A conjugate described herein can comprise one ormore linkers. The targeting ligand can be covalently linked to the metalchelator through a linker. The linker can covalently attach thetargeting ligand with the metal chelator. The targeting ligand can alsoattach directly to the metal chelator without a linker.

A linker can comprise one or more amino acid residues. The linker cancomprise 1 to 3, 1 to 5, 1 to 10, 5 to 10, or 5 to 20 amino acidresidues. The linker can comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 aminoacid residues. The linker can comprise 1 to 5 amino acid residues. Forexample, the linker can comprise one or more lysine (K) residues such asK, KK, or KKK sequences. The linker can comprise a lysine or aderivative thereof. The linker can comprise a lysine. The linker cancomprise one or more amino acids that are unnatural amino acids.

A herein-described linker can attach to the N-terminus of the peptide,the C-terminus of the peptide, or a non-terminal amino acid of thepeptide, or it can attach to the peptide through a combination of theabove. In some embodiments, the linker is attached to the peptide viaits N-terminus. In some embodiments, the linker is attached to thepeptide via its C-terminus. In some embodiments, the linker is attachedto the peptide via a non-terminal amino acid. The linker can be bondedto the peptide, the metal chelator, or both, for example, through achemically reactive group. Exemplary chemically reactive groups include,but are not limited to, a free amino, imino, hydroxyl, thiol or carboxylgroup (e.g., to the N- or C-terminus, to the epsilon amino group of oneor more lysine residues, the free carboxylic acid group of one or moreglutamic acid or aspartic acid residues, or to the sulfhydryl group ofone or more cysteinyl residues). The site to which the linker is boundto the peptide can be a natural or unnatural amino acid of the peptideand/or it can be introduced into the peptide, e.g., by DNA recombinanttechnology (e.g., by introducing a cysteine or protease cleavage site inthe amino acid sequence) or by protein biochemistry (e.g., reduction, pHadjustment or proteolysis). Exemplary methods for attaching the linkerincludes carbodiimide reaction, reactions using bifunctional agents suchas dialdehydes or imidoesters, Schiff base reaction, Suzuki-Miyauracross-coupling reactions, Isothiocyanates as coupling agents, and clickchemistry.

The linker can have a prescribed length thereby linking the metalchelator (and optionally radionuclide) and the peptide while allowing anappropriate distance therebetween. In some embodiments, the linker has 1to 100 atoms, 1 to 60 atoms, 1 to 30 atoms, 1 to 15 atoms, 1 to 10atoms, 1 to 5, or 2 to 20 atoms in length. In some embodiments, thelinker has 1 to 10 atoms in length.

The linker can comprise flexible and/or rigid regions. Exemplaryflexible linker regions include those comprising Gly and Ser residues(“GS” linker), glycine residues, alkylene chain, PEG chain, etc.Exemplary rigid linker regions include those comprising alphahelix-forming sequences (e.g., EAAAK (SEQ ID NO: 104)), proline-richsequences, and regions rich in double and/or triple bonds.

In some embodiments, the linker comprises a click chemistry residue. Thelinker can be attached to the peptide, to the metal chelator, or bothvia click chemistry, thereby forming a click chemistry residue. Forexample, the peptide can comprise an azide group (at N- or C-terminus orat a non-terminal amino acid) that reacts with an alkyne moiety of thelinker. For another example, the peptide can comprise an alkyne group(at N- or C-terminus or at a non-terminal amino acid) that reacts withan azide of the linker. The metal chelator and the linker can beattached similarly. In some embodiments, the linker comprises an azidemoiety, an alkyne moiety, or both.

A linker described herein can comprise one or more motifs. One or moreof the motifs can be connected via click chemistry such that they can beclicked in/out of the linker. Each of the motifs in a linker can haveindependent functions. For example, a linker can comprise a motif thatfunctions to adjust plasma half-life and/or a motif that functions as aspacer between the peptide and metal chelator.

In some embodiments, the linker has a structure of

wherein each L is independently —O—, —NR^(L)—, —N(R^(L))₂ ⁺-,—OP(═O)(OR^(L))O—, —S—, —S(═O)—, —S(═O)₂—, ═CH—, —C(═O)—, —C(═O)O—,—OC(═O)—, —OC(═O)O—, —C(═O)NR^(L)—, —NR^(L)C(═O)—, —OC(═O)NR^(L)—,—NR^(L))═O)O—, NR^(L)C(═O)NR^(L)—, —NR^(L)C(═S)NR^(L)—, —CR^(L)═N—,—N═CR^(L), —NR^(L)S(═O)₂—, —S(═O)₂NR^(L)—, —C(═O)NR^(L)S(═O)₂—,—S(═O)₂NR^(L)C(═O)—, substituted or unsubstituted C₁-C₃₀ alkylene,substituted or unsubstituted C₂-C₃₀ alkenylene, substituted orunsubstituted C₂-C₃₀ alkynylene, substituted or unsubstituted C₁-C₃₀heteroalkylene, —(C₁-C₃₀ alkylene)-O—, —O—(C₁-C₃₀ alkylene)-, —(C₁-C₃₀alkylene)-NR^(L)—, —NR^(L)—(C₁-C₃₀ alkylene)-, —(C₁-C₃₀alkylene)-N(R^(L))₂ ⁺—, —N(R^(L))₂ ⁺—(C₁-C₃₀ alkylene)-, or a clickchemistry residue; and each R^(L) is independently hydrogen, substitutedor unsubstituted C₁-C₄ alkyl, substituted or unsubstituted C₁-C₄heteroalkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₂-C₅ alkynyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or15.Isomers/Stereoisomers

In some embodiments, the compounds described herein exist as geometricisomers. In some embodiments, the compounds described herein possess oneor more double bonds. The compounds presented herein include cis, trans,syn, anti, entgegen (E), and zusammen (Z) isomers as well as thecorresponding mixtures thereof. In some situations, the compoundsdescribed herein possess one or more chiral centers and each centerexists in the R configuration or S configuration. The compoundsdescribed herein include diastereomeric, enantiomeric, and epimericforms as well as the corresponding mixtures thereof. In additionalembodiments of the compounds and methods provided herein, mixtures ofenantiomers and/or diastereoisomers, resulting from a single preparativestep, combination, or interconversion are useful for the applicationsdescribed herein. In some embodiments, the compounds described hereinare prepared as their individual stereoisomers by reacting a racemicmixture of the compound with an optically active resolving agent to forma pair of diastereoisomeric compounds, separating the diastereomers, andrecovering the optically pure enantiomers. In some embodiments,dissociable complexes are preferred. In some embodiments, thediastereomers have distinct physical properties (e.g., melting points,boiling points, solubilities, reactivity, etc.) and are separated bytaking advantage of these dissimilarities. In some embodiments, thediastereomers are separated by chiral chromatography, or preferably, byseparation/resolution techniques based upon differences in solubility.In some embodiments, the optically pure enantiomer is then recovered,along with the resolving agent.

Tautomers

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein, in certain embodiments, exist as tautomers.In circumstances where tautomerization is possible, a chemicalequilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

In some instances, the compounds disclosed herein exist in tautomericforms. The structures of said compounds are illustrated in the onetautomeric form for clarity. The alternative tautomeric forms areexpressly included in this disclosure.

Labeled Compounds.

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into compounds described herein, or a solvate, orstereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, sulfur, fluorine, and chloride, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Compounds described herein, and the pharmaceutically acceptable salts,solvates, or stereoisomers thereof which contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthis disclosure. Certain isotopically-labeled compounds, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H and carbon-14, i.e., ¹⁴C, isotopes arenotable for their ease of preparation and detectability. Further,substitution with heavy isotopes such as deuterium, i.e., ²H, producescertain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements. In some embodiments, the isotopically labeled compound ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof isprepared by any suitable method.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts.

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the compoundsdisclosed herein include their pharmaceutically acceptable salts. Asused herein, a “pharmaceutically acceptable salt” refers to any salt ofa stabilizing agent that is useful for stabilizing theradiopharmaceutical compositions. As used herein, a “pharmaceuticallyacceptable salt” refers to any salt of a stabilizing agent that isuseful for preventing or delaying the decomposition of theradiopharmaceutical within the compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds disclosed herein, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Examples of pharmaceutically acceptable salts include those saltsprepared by reaction of the compounds described herein with a mineralacid, organic acid, or inorganic base, such salts including acetate,acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate,camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride,citrate, cyclopentanepropionate, decanoate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate,γ-hydroxy butyrate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate,malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate,methoxybenzoate, methylbenzoate, monohydrogenphosphate,1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate,sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate,thiocyanate, tosylate, undeconate, and xylenesulfonate.

Further, the compounds described herein can be prepared aspharmaceutically acceptable salts formed by reacting the free base formof the compound with a pharmaceutically acceptable inorganic or organicacid, including, but not limited to, inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, metaphosphoric acid, and the like; and organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citricacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, and muconic acid.

In some embodiments, the compounds described herein which comprise afree acid group react with a suitable base, such as the hydroxide,carbonate, bicarbonate, or sulfate of a pharmaceutically acceptablemetal cation, with ammonia, or with a pharmaceutically acceptableorganic primary, secondary, tertiary, or quaternary amine.Representative salts include the alkali or alkaline earth salts, likelithium, sodium, potassium, calcium, and magnesium, and aluminum salts,and the like. Illustrative examples of bases include sodium hydroxide,potassium hydroxide, choline hydroxide, sodium carbonate, N⁺(C₁₋₄alkyl)₄, and the like.

Representative organic amines useful for the formation of base additionsalts include ethylamine, diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine, and the like. It should be understood thatthe compounds described herein also include the quaternization of anybasic nitrogen-containing groups they contain. In some embodiments,water or oil-soluble or dispersible products are obtained by suchquaternization.

Solvates.

In some embodiments, the compounds described herein exist as solvates.Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein can be conveniently prepared or formed duringthe processes described herein. In addition, the compounds providedherein can exist in unsolvated as well as solvated forms. In general,the solvated forms are considered equivalent to the unsolvated forms forthe purposes of the compounds and methods provided herein. Accordingly,one aspect of the present disclosure pertains to hydrates and solvatesof compounds of the present disclosure and/or their pharmaceuticalacceptable salts, as described herein, that can be isolated andcharacterized by methods known in the art, such as, thermogravimetricanalysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powderX-ray diffraction (PXRD), Karl Fisher titration, high resolution X-raydiffraction, and the like.

Preparation of the Compositions

The disclosure provides methods of preparing and making the compositionsdescribed herein. In some embodiments, the method of making theradiopharmaceutical composition comprises combining a radionuclide (suchas ²²⁵Ac) with a pre-labeled conjugate (e.g., DOTATATE or DOTATOC) inthe presence of one or more stabilizer agents, wherein the pre-labeledconjugate comprises a targeting ligand and a metal chelator covalentlyattached to the targeting ligand, thereby producing a mixture comprisinga labeled conjugate (e.g., ²²⁵Ac-DOTATATE or ²²⁵Ac-DOTATOC), andoptionally combining one or more stabilizing agents to the mixture. Insome embodiments, the method of making the radiopharmaceuticalcomposition comprises combining a radionuclide with a pre-labeledconjugate, wherein the pre-labeled conjugate comprises a targetingligand and a metal chelator covalently attached to the targeting ligand,thereby producing a labeled conjugate, and combining the one or morestabilizing agents with the labeled conjugate.

In some embodiments, the method of making the radiopharmaceuticalcomposition comprises combining a radionuclide with a pre-labeledconjugate, which further comprises a targeting ligand and a metalchelator covalently attached to the targeting ligand, thereby producinga labeled conjugate, and adding the one or more stabilizing agents tothe labeled conjugate. In some embodiments, the method of making theradiopharmaceutical composition comprises combining a radionuclide witha pre-labeled conjugate which further comprises a targeting ligand and ametal chelator covalently attached to the targeting ligand, in thepresence of one or more stabilizer agents, thereby producing a labeledconjugate, and optionally adding one or more stabilizing agents to thelabeled conjugate.

The method of making the compositions can comprise one or multiplesteps. One or more such steps can comprise diluting aradionuclide-containing solution or mixture to a desired concentration(i.e., a dilution step). The radionuclide-containing solution or mixturecan be diluted by 2 to 1000 fold, e.g., 10-50 fold, 2-40 fold, 25-75fold, or 50-100 fold. One or more such steps can comprise adding one ormore stabilizing agents during the process of dilution. One or more suchsteps can comprise optionally adding one or more stabilizing agentsduring the process of dilution. One or more such steps can comprisediluting a pre-labeled conjugate solution or mixture to a desiredconcentration. One or more such steps can comprise adding one or morestabilizing agents before the process of dilution. One or more suchsteps can comprise adding one or more stabilizing agents after theprocess of dilution. The pre-labeled conjugate can comprise a targetingligand and a metal chelator. The targeting ligand and the metal chelatorcan be linked covalently. One or more such steps can comprise dilutionusing a liquid solution or mixture.

A method of making a radiopharmaceutical composition can comprisereacting or combining a radionuclide with a pre-labeled conjugatesolution or mixture to obtain a labeled conjugate solution or mixture(i.e., a labeling process). In some embodiments, the method comprisesmaintaining a temperature during the labeling process. In someembodiments, the method comprises maintaining a temperature ranging from0° C. to 100° C., from 10° C. to 100° C., from 20° C. to 100° C., from30° C. to 100° C., from 40° C. to 100° C., from 50° C. to 100° C., from60° C. to 100° C., from 70° C. to 100° C., or from 80° C. to 100° C. Insome embodiments, the method comprises reacting the radionuclide withthe pre-labeled conjugate for a period of time. In some embodiments, theperiod of time is from about 1 minute to about 3 hours, from about 2minutes to about 2.5 hours, from about 3 minutes to about 2 hours, fromabout 5 minutes to about 1.5 hours, from about 8 minutes to about 1hours, or from about 10 minutes to about 30 minutes. In someembodiments, the method comprises mixing the radionuclide with thepre-labeled conjugate during the labeling process. One or more suchsteps can comprise mixing using laboratory mixing equipment such as amixer, a vortex mixer, a stirrer, a magnetic stirrer, a spinner, ashaker, a centrifuge, or a homogenizer. One or more such steps cancomprise shaking the reaction solution or mixture. One or more suchsteps can comprise shaking the reaction solution or mixture at a speedranging from about 10 rpm to about 5000 rpm, from about 100 rpm to about2500 rpm, from about 200 rpm to about 1000 rpm, from about 300 rpm toabout 800 rpm, or from about 400 rpm to about 600 rpm. One or more suchsteps can comprise further diluting the labeled conjugate solution ormixture. One or more such steps can comprise adding one or morestabilizing agents during the process of dilution. One or more suchsteps can comprise optionally adding one or more stabilizing agentsafter the process of dilution.

In some embodiments, a radiopharmaceutical composition comprising[²²⁵Ac]Ac-DOTA-TATE (or ²²⁵Ac-DOTA-TATE) can be prepared by reactingDOTA-TATE with [²²⁵Ac]AcCl₃ from HCl (e.g., 0.04M, aqueous) solution.Accordingly, provide herein are methods of making a radiopharmaceuticalcomposition comprising ²²⁵Ac-DOTA-TATE. In some embodiments, the methodcomprises one or more of the following steps: diluting DOTA-TATE withsodium acetate/acetic acid buffer solution, adding [²²⁵Ac]AcCl₃ HClsolution to the diluted DOTA-TATE, mixing the mixture, heating themixture, and diluting into a formulation buffer with one or morestabilizing agents described herein. In some embodiments, theconcentration of [²²⁵Ac]AcCl₃ in the HCl solution is about 10 μCi/μlHCl. In some embodiments, the concentration of [²²⁵Ac]AcCl₃ in the HClsolution is about 1 to 50 μCi/μl HCl.

In some embodiments, a method of making a radiopharmaceuticalcomposition comprising [²²⁵Ac]Ac-DOTA-TATE or [²²⁵Ac]Ac-DOTA-TOCcomprises one or more of the following steps: providing [²²⁵Ac]AcCl₃solution in a first vial, transferring such solution into a reactor,providing a reaction buffer solution into the first vial containing[²²⁵Ac]AcCl₃ solution, transferring the reaction buffer solution andresidual [²²⁵Ac]AcCl₃ solution from the first vial to the rector,transferring a DOTA-TATE or a DOTA-TOC solution into the reactor,reacting the DOTA-TATE or DOTA-TOC solution with [²²⁵Ac]AcCl₃ solutionin the reactor to obtain [²²⁵Ac]Ac-DOTA-TATE or [²²⁵Ac]Ac-DOTA-TOC, anddiluting the [²²⁵Ac]Ac-DOTA-TATE or [²²⁵Ac]Ac-DOTA-TOC in a formulationbuffer comprising one or more stabilizing agents described herein toform the radiopharmaceutical composition. In some embodiments, the molarratio of ²²⁵Ac to DOTA-TATE or DOTA-TOC is from 1:1 to 1:10, from 1:1 to1:8, from 1:1 to 1:5, from 1:1 to 1:3.5, from 1:1 to 1:2, or from 1:1 to1.25. In some embodiments, the molar ratio of ²²⁵Ac to DOTA-TATE orDOTA-TOC is about 1:1, 1:2, 1:25, 1:3, 1:3.5 or 1:4.

The compounds used in the reactions and compositions described hereinare made according to organic synthesis techniques known to thoseskilled in this art, starting from commercially available chemicalsand/or from compounds described in the chemical literature.“Commercially available chemicals” are obtained from standard commercialsources including ABX advanced biochemical compounds GmbH (Radeberg,Germany), Acros Organics (Pittsburgh, Pa.), Aldrich Chemical (Milwaukee,Wis., including Sigma Chemical and Fluka), Apin Chemicals Ltd. (MiltonPark, U.K.), Avidity Science (U.S.A.), Avocado Research (Lancashire,U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), ChemService Inc. (West Chester, Pa.), Crescent Chemical Co. (Hauppauge,N.Y.), Eastman Organic Chemicals, Eastman Kodak Company (Rochester,N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.), Fisons Chemicals(Leicestershire, U.K.), Frontier Scientific (Logan, Utah), ICNBiomedicals, Inc. (Costa Mesa, Calif.), ITM (Munich, Germany), KeyOrganics (Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.),Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem,Utah), Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston,Tex.), Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Sigma-Aldrich (U.S.A.), Spectrum Quality Product, Inc. (NewBrunswick, N.J.), TCI America (Portland, Oreg.), Trans World Chemicals,Inc. (Rockville, Md.), VWR (Radnor, Pa., USA), Wako Chemicals USA, Inc.(Richmond, Va.), and Wuxi-Apptech Inc. (Shanghai, China).

Method of Treatment

In one aspect, the disclosure provides methods of treating a disease orcondition in a subject in need thereof. The methods can compriseadministering a radiopharmaceutical composition to the subject in needthereof. The methods can provide a therapeutic and/or prophylacticbenefit to a subject in need thereof comprising administering aradiopharmaceutical composition described herein.

The methods can comprise administering to a subject aradiopharmaceutical composition that comprise a therapeuticallyeffective amount of a conjugate or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the subject has cancer. The cancercan be a solid tumor and/or an SSR-associated cancer.

In some embodiments, provided herein are methods for killing a cellcomprising contacting the cell with a conjugate or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, the cellexpresses a receptor described herein. In some embodiments, theconjugate or pharmaceutically acceptable salt or solvate thereof bindsto a structure on the cell. In some embodiments, the conjugate orpharmaceutically acceptable salt or solvate thereof releases a number ofalpha particles by natural radioactive decay. In some embodiments, theconjugate or pharmaceutically acceptable salt or solvate thereofreleases a number of beta particles, gamma rays, and/or Auger electronsby natural radioactive decay. The conjugate described herein can kill acell by radiation. In some embodiments, the conjugate kills the celldirectly by radiation. In some embodiments, the radiation creates, inthe cell, oxidized bases, abasic sites, single-stranded breaks,double-stranded breaks, DNA crosslink, chromosomal rearrangement, or acombination thereof. The conjugate can kill the cell by inducingdouble-stranded DNA breaks. The released alpha particles can besufficient to kill the cell. The released alpha particles can besufficient to stop cell growth. The conjugate can also kill the cellindirectly via the production of reactive oxygen species (ROS) such asfree hydroxyl radicals. In some embodiments, the conjugate kills thecell indirectly by releasing tumor antigens from one or more differentcells, which can have vaccine effect. The conjugate can kill the cell byabscopal effect. The cell can be a cancer cell. In some embodiments, themethod comprises killing a cell with an alpha-particle emittingradionuclide.

After contacting a cell, the described conjugate can be internalized bythe cell. The internalization can be mediated by cell receptors, cellmembrane endocytosis, etc. In some embodiments, rapid internalizationrate into cancer cells accompanied by a slow externalization rate canoffer therapeutic benefit.

In one aspect, the disclosed conjugate or a pharmaceutically acceptablesalt or solvate thereof is configured to treat cancer by ablating tumorcells. The conjugate or a pharmaceutically acceptable salt or solvatethereof may not modulate the biology of the tumor cell and/or thesurrounding stroma. The conjugate or a pharmaceutically acceptable saltor solvate thereof may not modulate immune cells. The ablating of tumorcells can lead to a downstream immunological cascade.

Non-limiting examples of cancers to be treated by the methods of thepresent disclosure can include melanoma (e.g., metastatic malignantmelanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer(e.g., hormone refractory prostate adenocarcinoma), pancreaticadenocarcinoma, breast cancer, colon cancer, lung cancer (e.g.,non-small cell lung cancer), esophageal cancer, squamous cell carcinomaof the head and neck, liver cancer, ovarian cancer, cervical cancer,thyroid cancer, glioblastoma, glioma, leukemia, lymphoma, and otherneoplastic malignancies. In some embodiments, a subject or population ofsubjects to be treated with a radiopharmaceutical composition of thepresent disclosure have a solid tumor. In some embodiments, a solidtumor is a melanoma, renal cell carcinoma, lung cancer, bladder cancer,breast cancer, cervical cancer, colon cancer, gall bladder cancer,laryngeal cancer, liver cancer, thyroid cancer, stomach cancer, salivarygland cancer, prostate cancer, pancreatic cancer, or Merkel cellcarcinoma. In some embodiments, a subject or population of subjects tobe treated with a radiopharmaceutical composition of the presentdisclosure have a hematological cancer. In some embodiments, the subjecthas a hematological cancer such as Diffuse large B cell lymphoma(“DLBCL”), Hodgkin's lymphoma (“HL”), Non-Hodgkin's lymphoma (“NHL”),Follicular lymphoma (“FL”), acute myeloid leukemia (“AML”), or Multiplemyeloma (“MM”). In some embodiments, a subject or population of subjectsto be treated having the cancer selected from the group consisting ofovarian cancer, lung cancer and melanoma. The cancer can be anSSTR1-associated cancer. The cancer can be an SSTR2-associated cancer.The cancer can be an SSTR3-associated cancer. The cancer can be anSSTR4-associated cancer. The cancer can be an SSTR5-associated cancer.The cancer can be a neuroendocrine cancer, a lymphatic cancer, apancreatic cancer, a pituitary cancer, a breast cancer, a stomachcancer, medulloblastoma, or neuroblastoma. The cancer can be aneuroendocrine cancer. The neuroendocrine cancer can be recurrent. Theneuroendocrine cancer can be refractory to a radiotherapy that comprisesbeta-particle emitting radionuclide. The neuroendocrine cancer can be aneuroendocrine lung cancer or a neuroendocrine pancreatic cancer. Theneuroendocrine cancer can be a Carcinoid tumor in the lungs,gastrointestinal tract or thymus, Pancreatic neuroendocrine tumor (e.g.,Gastrinoma, Insulinoma, Glucagonoma, VIPoma) Medullary thyroidcarcinoma, Merkel cell carcinoma, Pheochromocytoma of the adrenal gland,Adrenal cancer, Small cell carcinoma (such as in the lungs), or Largecell carcinoid tumor (such as in the lungs). In some embodiments, theneuroendocrine cancer can be a pancreatic neuroendocrine tumor (e.g.gastroenteropancreatic neuroendocrine tumor (GEP-NET)). In someembodiments, the neuroendocrine cancer can be a gastrointestinalneuroendocrine tumor (GI-NET). In some embodiments, the neuroendocrinecancer can be gastroesophageal pancreatic neuroendocrine tumor.

Gastroenteropancreatic neuroendocrine tumors, or GEP-NETs, are raretumors with an incidence in the U.S. of 5.45 cases per 100,000. Despitethis low incidence, many GEP-NETs follow a more indolent disease coursethan other epithelial malignancies and thus the prevalence of GEP-NETsin the U.S. is approximately 100,000. GEP-NET tumors can be aggressiveand resistant to therapy and based on the Surveillance, Epidemiology,and End Results database, metastatic disease is present at diagnosis in40-76% of cases. Depending on their morphology and proliferativeactivity, GEP-NETs can be classified as well-differentiated tumors orpoorly differentiated carcinomas. Well-differentiated GEP-NETs caninclude low-grade (Grade 1, defined as tumors with a mitotic rate of 0-1per 10 high power field, or HPF, or a Ki67 index from 0-2%) andintermediate-grade tumors (Grade 2, defined as tumors with a mitoticrate from 2-20 per 10 HPF or a Ki67 index from 3-20%), whereas poorlydifferentiated GEP-NETs can be high-grade (Grade 3, with a mitotic rategreater than 20 per 10 HPF or a Ki67 index greater than 20%).

In some embodiments, the site of primary NETs in the digestive tract isthe rectum, small intestine, pancreas, stomach, colon, and/or appendix.In some embodiments, the GEP-NET is categorized as hormonally functional(associated with signs and symptoms consistent with excess hormonesecretion). In some embodiments, the GEP-NET is categorized asnon-functional tumors, with clinical features and aggressivenessdepending on the primary tumor site. In some embodiments, the cancer ispancreatic neuroendocrine tumors (pNETs).

In some cases, a subject having GEP-NET has been treated with surgery.In some cases, a subject having GEP-NET is not suitable for surgerytreatment. In some cases, a subject having GEP-NET has developedmetastatic disease. In some embodiments, the GEP-NET overexpressessomatostatin receptor 2, or SSTR2 on the cell surface. In someembodiments, the subject has been previously treated with Somatostatinanalogs, or SSAs. In some embodiments, SSA is administered incombination with a conjugate described herein. In some embodiments, thesubject has been previously treated with chemotherapy and molecularlytargeted therapies such as everolimus or sunitinib. In some embodiments,chemotherapy and molecularly targeted therapies such as everolimus orsunitinib is administered in combination with a conjugate describedherein.

In some embodiments, provided herein are methods and compositions fortreating a disease or condition. Exemplary disease or condition includesrefractory or recurrent malignancies whose growth may be inhibited usingthe methods of treatment of the present disclosure. In some embodiments,the disease or condition is a cancer. In some embodiments, the cancer isbreast cancer, head and neck squamous cell carcinoma, non-small celllung cancer, hepatocellular cancer, colorectal cancer, gastricadenocarcinoma, pancreatic neuroendocrine tumor (e.g.gastroenteropancreatic neuroendocrine tumor), melanoma, or advancedcancer. In some embodiments, a cancer to be treated by the methods oftreatment of the present disclosure is selected from the groupconsisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcomata,endometrial cancer, breast cancer, ovarian cancer, cervical cancer,fallopian tube cancer, primary peritoneal cancer, colon cancer,colorectal cancer, squamous cell carcinoma of the anogenital region,melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer,squamous cell carcinoma of the lung, stomach cancer, bladder cancer,gall bladder cancer, liver cancer, thyroid cancer, laryngeal cancer,salivary gland cancer, esophageal cancer, head and neck cancer,glioblastoma, glioma, squamous cell carcinoma of the head and neck,prostate cancer, pancreatic cancer, pancreatic neuroendocrine tumors,gastroenteropancreatic neuroendocrine tumors, mesothelioma, sarcoma,hematological cancer, leukemia, lymphoma, neuroma, and combinationsthereof. In some embodiments, a cancer to be treated by the methods ofthe present disclosure include, for example, carcinoma, squamouscarcinoma (for example, cervical canal, eyelid, tunica conjunctiva,vagina, lung, oral cavity, skin, urinary bladder, tongue, larynx, andgullet), and adenocarcinoma (for example, prostate, small intestine,endometrium, cervical canal, large intestine, lung, pancreas, gullet,rectum, uterus, stomach, mammary gland, and ovary). In some embodiments,the cancer is GEP-NET. In some embodiments, a cancer to be treated bythe methods of the present disclosure further include sarcomata (forexample, myogenic sarcoma), leukosis, neuroma, melanoma, and lymphoma.In some embodiments, a cancer to be treated by the methods of thepresent disclosure is breast cancer. In some embodiments, a cancer to betreated by the methods of treatment of the present disclosure is triplenegative breast cancer (TNBC). In some embodiments, a cancer to betreated by the methods of treatment of the present disclosure ispancreatic cancer. In some embodiments, a cancer to be treated by themethods of treatment of the present disclosure is a pancreaticneuroendocrine tumor. In some embodiments, a cancer to be treated by themethods of treatment of the present disclosure is agastroenteropancreatic neuroendocrine tumor. In some embodiments, acancer to be treated by the methods of treatment of the presentdisclosure is GEP-NET. In some embodiments, a cancer to be treated bythe methods of treatment of the present disclosure is gastroesophagealpancreatic neuroendocrine tumor.

In addition to the methods of treatment described above, theradiopharmaceutical compositions described herein can be used to image,and/or as part of a treatment for diseases. Conjugates for imagingapplications, e.g., single-photon emission computed tomography (SPECT)and positron emission tomography (PET), can comprise a radionuclidesuitable for use as imaging isotopes such as the isotopes in Table 5B.Accordingly, the conjugate can be administered as a companiondiagnostic.

In one aspect, provided herein are methods for diagnosing a patientharboring an SSR expressing cancer or tumor comprising administering tothe patient a radiopharmaceutical described herein, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition comprising the same. In one aspect, provided herein aremethods for imaging an SSR expressing cancer or tumor comprisingadministering to the patient a radiopharmaceutical described herein, ora pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition comprising the same. In some embodiments, themethod further comprises selecting or confirming that a tumor in thepatient expresses SSR. In some embodiments, the SSR expressing cancer isan SSTR2 expressing cancer. In some embodiments, the method furthercomprises measuring the concentration of the radiopharmaceuticalaccumulated in the patient. In some embodiments, the method furthercomprises measuring the amount of radiation emitted from theradionuclide. In some embodiments, the method further comprisesanalyzing the elimination or clearance profile of theradiopharmaceutical in the patient. In some embodiments, the methodfurther comprises measuring an elimination half-life of theradiopharmaceutical in the patient. In some embodiments, the methodfurther comprises analyzing the clearance profile of theradiopharmaceutical in the patient. In some embodiments, the method ofimaging or diagnosing cancer comprises administering aradiopharmaceutical that comprises a radionuclide of Table 5B, such as⁶⁸Ga. For example, radiopharmaceuticals of the present disclosure can beadministered for patient selection purposes, such as to confirm thetumor has the appropriate expression of the SSR target (e.g., SSTR2). Asanother example, radiopharmaceuticals of the present disclosure can beadministered to a patient so that the patient's care team can make surethe radiopharmaceutical is cleared from the body in a suitable timeframeso that undesired irradiation of other tissues is minimized.

In some embodiments, a method described herein comprises administeringto a patient two radiopharmaceuticals of the present disclosure. In someembodiments, the two radiopharmaceuticals can have the same targetingligand. In some embodiments, a method described herein comprisesadministering (i) a radiopharmaceutical of the present disclosure thatcomprises a radionuclide of Table 5B, and followed by (i) aradiopharmaceutical of the present disclosure that comprises aradionuclide of Table 5A. In some embodiments, the method comprisesadministering ⁶⁸Ga-DOTA-TATE and followed by the administering of²²⁵Ac-DOTA-TATE.

The subject can be 4 to 120 years old. The subject can be 5 to 10, 5 to15, 5 to 18, 5 to 25, 5 to 35, 5 to 45, 5 to 55, 5 to 65, 5 to 75, 10 to15, 10 to 18, 10 to 25, 10 to 35, 10 to 45, 10 to 55, 10 to 65, 10 to75, 15 to 18, 15 to 25, 15 to 35, 15 to 45, 15 to 55, 15 to 65, 15 to75, 18 to 25, 18 to 35, 18 to 45, 18 to 55, 18 to 65, 18 to 75, 25 to35, 25 to 45, 25 to 55, 25 to 65, 25 to 75, 35 to 45, 35 to 55, 35 to65, 35 to 75, 45 to 55, 45 to 65, 45 to 75, 55 to 65, 55 to 75, or 65 to75 years old. The subject can be at least 5, 10, 15, 18, 25, 35, 45, 55,or 65 years old. The subject can be at most 10, 15, 18, 25, 35, 45, 55,65, or 75 years old. In some embodiments, the subject has not received aradiotherapy that comprises beta-particle emitting radionuclide prior tothe administering of the radiopharmaceutical composition. In someembodiments, the subject has not received a radiotherapy that comprisesalpha-particle emitting radionuclide prior to the administering of theradiopharmaceutical composition. In some embodiments, the subject hasreceived a radiotherapy that comprises alpha-particle emittingradionuclide prior to the administering of the radiopharmaceuticalcomposition. In some embodiments, the subject has received aradiotherapy that comprises beta-particle emitting radionuclide prior tothe administering of the radiopharmaceutical composition. In someembodiments, the subject has progressive disease following aradiotherapy treatment that comprises beta-particle emittingradionuclide (e.g., a ¹⁷⁷Lu labeled somatostatin analog) prior to theadministering of the radiopharmaceutical composition. In someembodiments, the subject has previously received ¹⁷⁷Lu-DOTA-TATEtreatment. In some embodiments, the subject has previously received¹⁷⁷Lu-DOTA-TOC treatment. In some embodiments, the subject has notreceived a therapy comprising a platinum based therapeutic prior to theadministering of the radiopharmaceutical composition. In someembodiments, the subject has not received a therapy comprising an immunecheckpoint inhibitor prior to the administering of theradiopharmaceutical composition.

Combination Therapy

In some embodiments, the radiopharmaceutical composition describedherein can be administered alone or in combination with one or moreadditional therapeutic agents. For example, the combination therapy caninclude a composition comprising a radiopharmaceutical compositiondescribed herein co-formulated with, and/or co-administered with, one ormore additional therapeutic agents, e.g., one or more anti-canceragents, e.g., cytotoxic or cytostatic agents, immune checkpointinhibitors, hormone treatment, vaccines, and/or immunotherapies. In someembodiments, the radiopharmaceutical composition is administered incombination with other therapeutic treatment modalities, includingsurgery, cryosurgery, and/or chemotherapy. Such combination therapiesmay advantageously utilize lower dosages of the administered therapeuticagents, thus avoiding possible toxicities or complications associatedwith the various monotherapies.

When administered in combination, two (or more) different treatments canbe delivered to the subject during the course of the subject'saffliction with the disorder, e.g., the two or more treatments aredelivered after the subject has been diagnosed with the disorder andbefore the disorder has been cured or eliminated. In some embodiments,the delivery of one treatment is still occurring when the delivery ofthe second begins, so that there is overlap. This is sometimes referredto herein as “simultaneous” or “concurrent delivery.” In someembodiments, the delivery of one treatment ends before the delivery ofthe other treatment begins. In some embodiments of either case, thetreatment is more effective because of combined administration. Forexample, the second treatment is more effective, e.g., an equivalenteffect is seen with less of the second treatment, or the secondtreatment reduces symptoms to a greater extent, than would be seen ifthe second treatment were administered in the absence of the firsttreatment, or the analogous situation is seen with the first treatment.In some embodiments, delivery is such that the reduction in a symptom,or other parameter related to the disorder is greater than what would beobserved with one treatment delivered in the absence of the other. Theeffect of the two treatments can be partially additive, wholly additive,or greater than additive. The delivery can be such that an effect of thefirst treatment delivered is still detectable when the second isdelivered.

In some embodiments, the herein-described conjugate is used incombination with a chemotherapeutic agent, e.g., a DNA damagingchemotherapeutic agent. Non-limiting examples of DNA damagingchemotherapeutic agents include topoisomerase I inhibitors,topoisomerase II inhibitors; alkylating agents; DNA intercalators; DNAintercalators and free radical generators such as bleomycin; andnucleoside mimetics. In some embodiments, the herein-described conjugateis used in combination with a radiation sensitizer, which makes tumorcells more sensitive to radiation therapy. In some embodiments, theherein-described conjugate is used in combination with a DNA damagerepair inhibitor (or DNA damage response (DDR) inhibitor).

In some embodiments, a herein-described conjugate is used in combinationwith one or more of a chemotherapeutic agents (e.g., Everolimus,Sunitinib). In some embodiments, a herein-described conjugate (such as²²⁵Ac-DOTA-TATE) is used in combination with Everolimus. In someembodiments, a herein-described conjugate (such as ²²⁵Ac-DOTA-TATE) isused in combination with Sunitinib.

In some embodiments, a herein-described conjugate is used in combinationwith a Somatostatin analog, such as octreotide and lanreotide

Co-administration of amino acids with a radiopharmaceutical describedherein may reduce kidney update of the radiopharmaceutical. In someembodiments, a radiopharmaceutical composition described herein isconcurrently administered with an intravenous infusion of one or moreamino acids. In some embodiments, a radiopharmaceutical compositiondescribed herein is administered after an intravenous infusion of one ormore amino acids. In some embodiments, the infusion of the one or moreamino acids is administered at least 30 minutes prior to administering aradiopharmaceutical composition described herein. In some embodiments,the infusion of the one or more amino acids is administered at least 6hours, 3 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, or 5 minutesprior to administering a radiopharmaceutical composition describedherein. In some embodiments, the infusion of the one or more amino acidsis administered 10 to 60 minutes prior to administering aradiopharmaceutical composition described herein. In some embodiments,the concentration of the one or more amino acids is about 0.5% to about10% w/v. In some embodiments, the concentration of the one or more aminoacids is about 0.1% to about 25% w/v. In some embodiments, theconcentration of the one or more amino acids is about 1% to about 5%w/v. In some embodiments, the concentration of the one or more aminoacids is about 1% to about 3% w/v. In some embodiments, aradiopharmaceutical described herein is concurrently administered withan infusion of arginine and lysine. In some embodiments, aradiopharmaceutical described herein is concurrently administered withan intravenous infusion of arginine hydrochloride and lysinehydrochloride, where the concentration of arginine hydrochloride andlysine hydrochloride is about 2% w/v to about 5% w/v. In someembodiments, a radiopharmaceutical described herein is concurrentlyadministered with an intravenous infusion of arginine hydrochloride andlysine hydrochloride, where the concentration of arginine hydrochlorideand lysine hydrochloride is about 2.5% w/v. In some embodiments, theintravenous infusion of arginine and lysine is administered beforeadministering a radiopharmaceutical described herein. In someembodiments, the intravenous infusion is administered at least 30minutes prior to administering a radiopharmaceutical described herein.In some embodiments, the intravenous infusion is administered at least30 minutes prior to administering a radiopharmaceutical described hereinand is continually administered for up to 4 hours total.

Administration

The radiopharmaceutical compositions of the current disclosure can beadministered by any suitable means, including oral, topical (includingbuccal and sublingual), rectal, vaginal, transdermal, parenteral,subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecaland epidural and intranasal, and, if desired for local treatment,intralesional administration. The term parenteral as used hereinincludes e.g., subcutaneous, intravenous, intramuscular, intrasternal,intraperitoneal, and infusion techniques. The term parenteral alsoincludes injections, into the eye or ocular, intravitreal, intrabuccal,transdermal, intranasal, into the brain, including intracranial andintradural, into the joints, including ankles, knees, hips, shoulders,elbows, wrists, and the like, and in suppository form. Theradiopharmaceutical compositions can be administered orally. Theradiopharmaceutical compositions can be administered by systemicadministration. The radiopharmaceutical compositions can be administeredparenterally. The radiopharmaceutical compositions can be administeredlocally at a targeted site.

The radiopharmaceutical compositions described herein can beadministered via parenteral injection as liquid solution, which caninclude other chemical components, such as carriers, stabilizers,diluents, dispersing agents, suspending agents, thickening agents,preservatives, or excipients. Parenteral injections can be formulatedfor bolus injection or continuous infusion. The radiopharmaceuticalcompositions can be formulated in a form suitable for parenteralinjection as a sterile suspension, solution or emulsion in oily oraqueous vehicles, and can contain formulatory agents such as suspending,stabilizing or dispersing agents. The radiopharmaceutical formulationsfor parenteral administration can comprise aqueous solutions of theactive compounds in water soluble form. Solutions or suspensions usedfor parenteral, intradermal, or subcutaneous application can include: asterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid, gentisic acid, orsodium bisulfate; chelating agents such as ethylenediaminetetraaceticacid; buffers such as acetates, citrates or phosphates; surfactants suchas polysorbate 80; and agents for the adjustment of tonicity such assodium chloride or dextrose. pH can be adjusted with acids or bases,such as hydrochloric acid or sodium hydroxide. In some embodiments, theradiopharmaceutical composition comprises a reductant. The presence of areductant can help minimize potential radiolysis. In some embodiments,the reductant is ascorbic acid, gentisic acid, sodium thiosulfate,citric acid, tartaric acid, or a combination thereof.

The radiopharmaceutical compositions can be administered in a mannerappropriate to the disease to be treated. An appropriate dose and asuitable duration and frequency of administration can be determined bysuch factors as the condition of the subject, the type and severity ofthe subject's disease, the particular form of the active ingredient, andthe method of administration. In some embodiments, an appropriate doseand treatment regimen provides the composition(s) in an amountsufficient to provide therapeutic and/or prophylactic benefit (e.g., animproved clinical outcome), or a lessening of symptom severity. Optimaldoses are generally determined using experimental models and/or clinicaltrials. The optimal dose depends upon the body mass, weight, or bloodvolume of the subject. In some embodiments, the radiopharmaceuticalcompositions can be administered as part of a first-line therapy. Insome embodiments, the radiopharmaceutical compositions can beadministered as part of a first-line therapy with existing standard ofcare, for example, immune checkpoint blockers and DNA damaging agents.

The radiopharmaceutical compositions administered can comprise amountsof conjugates or pharmaceutically acceptable salts or solvates thereofsufficient to deliver a therapeutically effective dose of the particularsubject. In some embodiments, the dosage of the conjugate is betweenabout 0.1 pg and about 50 mg per kilogram of body weight, between about1 μg and about 50 mg per kilogram of body weight, or between about 0.1and about 10 mg per kilogram of body weight. Therapeutically effectivedosages can also be determined at the discretion of a physician. By wayof example only, the radiopharmaceutical compositions administered cancomprise dose of the conjugate or a pharmaceutically acceptable salt orsolvate thereof for methods of treating a disease as described herein isabout 0.001 mg/kg to about 1 mg/kg body weight of the subject per dose.In some embodiments, the dose of conjugate or a pharmaceuticallyacceptable salt or solvate thereof for the described methods is about0.001 mg to about 1000 mg per dose for the subject being treated. Insome embodiments, a conjugate or a pharmaceutically acceptable salt orsolvate thereof described herein is administered to a subject at adosage of from about 0.01 mg to about 500 mg, from about 0.01 mg toabout 100 mg, or from about 0.01 mg to about 50 mg. In some embodiments,a conjugate or a pharmaceutically acceptable salt or solvate thereofdescribed herein is administered to a subject at a dosage of about 0.01picomole to about 1 mole, about 0.1 picomole to about 0.1 mole, about 1nanomole to about 0.1 mole, or about 0.01 micromole to about 0.1millimole. In some embodiments, a conjugate or a pharmaceuticallyacceptable salt or solvate thereof described herein is administered to asubject at a dosage of about 0.0001 Gbq to about 1000 Gbq, 0.01 Gbq toabout 1000 Gbq, about 0.5 Gbq to about 100 Gbq, or about 1 Gbq to about50 Gbq. In some embodiments, the radiopharmaceutical composition (or aconjugate or a pharmaceutically acceptable salt or solvate thereof) isadministered to a subject in an amount equivalent to about 1 kBq/kg toabout 100,000 kBq/kg, about 5 kBq/kg to about 50,000 kBq/kg, about 20 kBq/kg to about 5,000 kBq/kg, about 50 k Bq/kg to about 500 kBq/kg, about50 k Bq/kg to about 200 kBq/kg, or about 70 kBq/kg to about 150 kBq/kgbody weight per dose. In some embodiments, the radiopharmaceuticalcomposition (or a conjugate or a pharmaceutically acceptable salt orsolvate thereof) is administered in an amount equivalent to about 1kBq/kg to about 100,000 kBq/kg body weight per dose. Theradiopharmaceutical compositions administered to a subject can comprisea conjugate or a pharmaceutically acceptable salt or solvate thereof inan amount equivalent to about 5 kBq/kg to about 50,000 kBq/kg bodyweight per dose. The radiopharmaceutical compositions administered to asubject can comprise a conjugate or a pharmaceutically acceptable saltor solvate thereof in an amount equivalent to about 20 kBq/kg to about5,000 kBq/kg body weight per dose. The radiopharmaceutical compositionsadministered to a subject can comprise a conjugate or a pharmaceuticallyacceptable salt or solvate thereof in an amount equivalent to about 50 kBq/kg to about 500 kBq/kg body weight per dose. The radiopharmaceuticalcompositions administered to a subject can comprise a conjugate or apharmaceutically acceptable salt or solvate thereof in an amountequivalent to about 70 kBq/kg to about 150 kBq/kg body weight per dose.In some embodiments, the radiopharmaceutical compositions administeredto a subject can comprise a conjugate or a pharmaceutically acceptablesalt or solvate thereof in an amount equivalent to about 30 kBq/kg toabout 150 kBq/kg body weight per dose. In some embodiments, theradiopharmaceutical compositions administered to a subject can comprisea conjugate or a pharmaceutically acceptable salt or solvate thereof inan amount equivalent to about 90 kBq/kg to about 180 kBq/kg body weightper dose. In some embodiments, the radiopharmaceutical compositionsadministered to a subject can comprise a conjugate or a pharmaceuticallyacceptable salt or solvate thereof in an amount equivalent to about 30kBq/kg to about 240 kBq/kg body weight per dose. In some embodiments,the radiopharmaceutical compositions administered to a subject cancomprise a conjugate or a pharmaceutically acceptable salt or solvatethereof in an amount equivalent to about 60 kBq/kg to about 120 kBq/kgbody weight per dose. In some embodiments, the radiopharmaceuticalcomposition (or a conjugate or a pharmaceutically acceptable salt orsolvate thereof) is administered to a subject in an amount equivalent toabout 120 kBq/kg body weight per dose. In some embodiments, theradiopharmaceutical composition (or a conjugate or a pharmaceuticallyacceptable salt or solvate thereof) is administered to a subject in anamount equivalent to about 90 kBq/kg body weight per dose. In someembodiments, the radiopharmaceutical composition (or a conjugate or apharmaceutically acceptable salt or solvate thereof) is administered toa subject in an amount equivalent to about 60 kBq/kg body weight perdose. The radiopharmaceutical composition can be administered to thesubject to achieve a cumulative dose of conjugate or pharmaceuticallyacceptable salt of solvate thereof in an equivalent of about 1,000 kBqto about 5,000,000 kBq. The radiopharmaceutical composition can beadministered to the subject to achieve a cumulative dose of conjugate orpharmaceutically acceptable salt of solvate thereof in an equivalent ofabout 5,000 kBq to about 1,000,000 kBq. The radiopharmaceuticalcomposition can be administered to the subject to achieve a cumulativedose of conjugate or pharmaceutically acceptable salt of solvate thereofin an equivalent of about 8,000 kBq to about 5,000,000 kBq. Theradiopharmaceutical composition can be administered to the subject toachieve a cumulative dose of conjugate or pharmaceutically acceptablesalt of solvate thereof in an equivalent of about 10,000 kBq to about100,000 kBq. The radiopharmaceutical composition can be administered tothe subject to achieve a cumulative dose of conjugate orpharmaceutically acceptable salt of solvate thereof in an equivalent ofabout 20,000 kBq to about 90,000 kBq. The radiopharmaceuticalcomposition can be administered to the subject to achieve a cumulativedose of conjugate or pharmaceutically acceptable salt of solvate thereofin an equivalent of about 40,000 kBq to about 70,000 kBq. In someembodiments, the radiopharmaceutical composition can be administered tothe subject to achieve a cumulative dose of conjugate orpharmaceutically acceptable salt or solvate thereof in an equivalent ofabout 400 kBq to about 4,000,000 kBq. In some embodiments, theradiopharmaceutical composition can be administered to the subject toachieve a cumulative dose of conjugate or pharmaceutically acceptablesalt or solvate thereof in an equivalent of about 20,000 kBq to about40,000 kBq. In some embodiments, the radiopharmaceutical composition canbe administered to the subject to achieve a cumulative dose of conjugateor pharmaceutically acceptable salt or solvate thereof in an equivalentof about 20,000 kBq to about 30,000 kBq. In some embodiments, theradiopharmaceutical composition can be administered to the subject toachieve a cumulative dose of conjugate or pharmaceutically acceptablesalt or solvate thereof in an equivalent of about 30,000 kBq to about40,000 kBq. In some embodiments, the radiopharmaceutical composition canbe administered to the subject to achieve a cumulative dose of conjugateor pharmaceutically acceptable salt or solvate thereof in an equivalentof about 40,000 kBq to about 50,000 kBq. In some embodiments, theradiopharmaceutical composition can be administered to the subject toachieve a cumulative dose of conjugate or pharmaceutically acceptablesalt or solvate thereof in an equivalent of about 40,000 kBq to about100,000 kBq. In some embodiments, the radiopharmaceutical compositioncan be administered to the subject to achieve a maximum cumulative doseof conjugate or pharmaceutically acceptable salt or solvate thereof inan equivalent of about 60,000 kBq. In some embodiments, theradiopharmaceutical composition can be administered to the subject toachieve a maximum cumulative dose of conjugate or pharmaceuticallyacceptable salt or solvate thereof in an equivalent of about 40,800 kBq.In some embodiments, the dose is administered once a day, 1 to 3 times aweek, 1 to 4 times a month, or 1 to 12 times a year. Theradiopharmaceutical compositions can be administered at a 2-weekinterval. The radiopharmaceutical compositions can be administered at a4-week interval. The radiopharmaceutical compositions can beadministered at a 6-week interval. The radiopharmaceutical compositionscan be administered at an 8-week interval. The radiopharmaceuticalcompositions can be administered at a 10-week interval. Theradiopharmaceutical compositions can be administered at a 12-weekinterval. The radiopharmaceutical compositions can be administered at a15-week interval. The radiopharmaceutical composition can beadministered at a 20-week interval. The radiopharmaceutical compositioncan be administered in cycles. For example, the radiopharmaceuticalcomposition can be administered in 1-20 cycles. In some embodiments, theradiopharmaceutical composition is administered for 1-10 cycles. In someembodiments, the radiopharmaceutical composition is administered for 1-5cycles. In some embodiments, the radiopharmaceutical composition isadministered for 3-9 cycles. In some embodiments, theradiopharmaceutical composition is administered for 1 cycle. In someembodiments, the radiopharmaceutical composition is administered for 2cycles. In some embodiments, the radiopharmaceutical composition isadministered for 3 cycles. In some embodiments, the radiopharmaceuticalcomposition is administered for 4 cycles. In some embodiments, theradiopharmaceutical composition is administered for 5 cycles. In someembodiments, the radiopharmaceutical composition is administered for 6cycles. In some embodiments, the radiopharmaceutical composition isadministered for 7 cycles. In some embodiments, the radiopharmaceuticalcomposition is administered for 8 cycles. In some embodiments, theradiopharmaceutical composition is administered for 9 cycles. In someembodiments, the radiopharmaceutical composition is administered for 10cycles. In some embodiments, the radiopharmaceutical composition isadministered for 11 cycles. In some embodiments, the radiopharmaceuticalcomposition is administered for 12 cycles. In some embodiments, eachcycle includes one administration every 8 weeks. In some embodiments,each cycle includes one administration every 4 weeks. In someembodiments, each cycle includes one administration every 6 weeks. Insome embodiments, each cycle includes one administration every 12 weeks.In some embodiments, the radiopharmaceutical composition comprises225Ac-DOTA-TATE.

The pharmaceutical compositions can be packaged in unit dosage form forease of administration and uniformity of dosage. A unit dosage form canrefer to physically discrete units suited as unitary dosages for thesubject to be treated; each unit containing a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the pharmaceutical carrier or excipient. In someembodiments, the unit dosage has a volume of 5 to 25 mL. In someembodiments, the unit dosage has a volume of 1 to 10 mL. In someembodiments, the unit dosage has a volume of 8 to 15 mL. In someembodiments, the unit dosage has a volume of 10 to 15 mL. In someembodiments, the unit dosage has a volume of 8 mL. In some embodiments,the unit dosage has a volume of 9 mL. In some embodiments, the unitdosage has a volume of 10 mL. In some embodiments, the unit dosage has avolume of 11 mL. In some embodiments, the unit dosage has a volume of 12mL. In some embodiments, the unit dosage has a volume of 13 mL. In someembodiments, the unit dosage has a volume of 14 mL. In some embodiments,the unit dosage has a volume of 15 mL. In some embodiments, the unitdosage has a volume of 16 mL. In some embodiments, the unit dosage has avolume of 17 mL. In some embodiments, the unit dosage has a volume of 18mL. In some embodiments, the unit dosage has a volume of 19 mL. In someembodiments, the unit dosage has a volume of 20 mL. In some embodiments,the unit dosage comprises ²²⁵Ac-DOTA-TATE in an amount equivalent to146-275 μCi. In some embodiments, the unit dosage comprises²²⁵Ac-DOTA-TATE in an amount equivalent to 100-300 μCi.

In some embodiments, the unit dosage comprises ²²⁵Ac-DOTA-TATE in anamount equivalent to 10-500 μCi. In some embodiments, the unit dosagecomprises ²²⁵Ac-DOTA-TATE in an amount equivalent to more than 500 μCi.In some embodiments, the unit dosage comprises ²²⁵Ac-DOTA-TATE in anamount equivalent to 10-100 μCi. In some embodiments, the unit dosagecomprises ²²⁵Ac-DOTA-TATE in an amount equivalent to 10-50 μCi. In someembodiments, the unit dosage comprises ²²⁵Ac-DOTA-TATE in an amountequivalent to 100-200 μCi. In some embodiments, the unit dosagecomprises ²²⁵Ac-DOTA-TATE in an amount equivalent to 120-300 μCi. Insome embodiments, the unit dosage comprises ²²⁵Ac-DOTA-TATE in an amountequivalent to 200-400 μCi. In some embodiments, the unit dosagecomprises ²²⁵Ac-DOTA-TATE in an amount equivalent to 200-500 μCi. Insome embodiments, the unit dosage comprises ²²⁵Ac-DOTA-TATE in an amountequivalent to 146-275 μCi. In some embodiments, the unit dosagecomprises ²²⁵Ac-DOTA-TATE in an amount equivalent to 146-275 μCi in a 12mL solution.

In some embodiments, the unit dosage comprises ²²⁵Ac-DOTA-TATE in anamount equivalent to 45-114 μg of DOTATATE. In some embodiments, theunit dosage comprises ²²⁵Ac-DOTA-TATE in an amount equivalent to 5 to1000 μg of DOTATATE. In some embodiments, the unit dosage comprises²²⁵Ac-DOTA-TATE in an amount equivalent to 0.5 to 10,000 μg of DOTATATE.In some embodiments, the unit dosage comprises ²²⁵Ac-DOTA-TATE in anamount equivalent to 20 to 200 μg of DOTATATE. In some embodiments, theunit dosage comprises ²²⁵Ac-DOTA-TATE in an amount equivalent to 10 to50 μg of DOTATATE. In some embodiments, the unit dosage comprises²²⁵Ac-DOTA-TATE in an amount equivalent to 50 to 150 μg of DOTATATE. Insome embodiments, the unit dosage comprises ²²⁵Ac-DOTA-TATE in an amountequivalent to 1 to 100 μg of DOTATATE. In some embodiments, the unitdosage comprises ²²⁵Ac-DOTA-TATE in an amount equivalent to 1 to 200 μgof DOTATATE. In some embodiments, the unit dosage comprises²²⁵Ac-DOTA-TATE in an amount equivalent to 100 to 500 μg of DOTATATE. Insome embodiments, the unit dosage comprises ²²⁵Ac-DOTA-TATE in an amountequivalent to 25 to 150 μg of DOTATATE. In some embodiments, the unitdosage comprises ²²⁵Ac-DOTA-TATE in an amount equivalent to about 10,15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100,105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, or 160 μg ofDOTATATE.

In some embodiments, radiopharmaceutical compositions described hereinare formulated in a unit dosage form stored in a glass vial.

In some embodiments, the radiopharmaceutical compositions describedherein can comprise compounds exist as solvates. This disclosureprovides for methods of treating diseases by administering suchsolvates. This disclosure further provides for methods of treatingdiseases by administering such solvates as radiopharmaceuticalcompositions.

Although the present disclosure and its advantages have been describedin detail, it should be understood that various changes, substitutionsand alterations can be made herein without departing from the spirit andscope of the disclosure as defined in the appended claims.

The present disclosure is further illustrated in the following Exampleswhich are given for illustration purposes only and are not intended tolimit the disclosure in any way.

EXAMPLES Example 1. Conjugate Synthesis

A typical procedure to synthesize of [²²⁵Ac]Ac-DOTA-TATE was achieved byreacting DOTA-TATE acetate (28 μg, 28 μt) from 1.0 mg/mL water solution)with [²²⁵Ac]AcCl₃ (6.8 MBq or 0.2 mCi, 22 μl) from 10 μCi/μl HCl (0.04M,aqueous) solution. The DOTA-TATE acetate was diluted to 150 μL withsodium acetate/acetic acid buffer solution (0.4 M, pH=6.50).[²²⁵Ac]AcCl₃ HCl solution was added. The reaction mixture of totalvolume of 200 μl was mixed with vortex mixture, then heated at 90° C.for 15 min at a shaking speed of 500 rpm. Upon completion, the mixturewas directly diluted into the desired formulation described below.

Radio-TLC was performed at time 0 hour to determine radiochemical yieldof the labeling reaction with the following protocol: 1 μL, of thereaction mixture was spotted onto a TLC plate (Agilent A120B12, platesize 11.4×2.0 cm) at 1.5 cm from the bottom edge. The TLC was developedwith 10 mM DTPA water solution (pH=7.0, adjusted by 1.0 M NaOH) untilthe eluent reaches 1.5 cm from the top edge (or in 15 mins). Afterdrying in an incubator at a temperature of 38° C., the radio-TLCconversion was analyzed at different time points with a radio-TLC reader(Eckert & Ziegler AR-2000) set at High Voltage=1000 (to ensure alphadetection) until the ratio between labeled product and the free Ac225ion no longer change (typically after 6-8 hours of TLC separation toensure equilibrium between Ac225 and daughter nuclides). The typicalradiochemical yield of [²²⁵Ac]Ac-DOTA-TATE syntheses were found >99.0(±0.5) %, Molar activity is 10 mCi/μmol.

Example 2. Broad Scope Screening of Excipients

Upon completion of the radiolabeling, the reaction mixture described inexample 1 was immediately diluted in the stabilizing formulation in30×fold (v/v), or to 0.03 mCi/ml. The formulations were buffered withsodium acetate-acetic acid 0.4 M solution to pH 5.80 (±0.10). A signalcomponent excipient as stabilizing agent at 1 mg/ml in the buffer,except EtOH where 10% (v/v) was presented. Sodium L-Ascorbate/L-Ascorbicacid buffer was adjusted to pH 5.80 (±0.10). Water for Injection (WFI)with the same dilution without any excipient is used as the controlformulation. The mixture was kept at room temperature (25° C.). Purityof [²²⁵Ac]Ac-DOTA-TATE was checked at different time points by radio-TLCas described in the table below. Purity is described as the ²²⁵Acpresent in [²²⁵Ac]Ac-DOTA-TATE divided by total ²²⁵Ac content at thattime point.

Percentage of ²²⁵AC present in [²²⁵Ac]Ac-DOTA-TATE 0 hour 24 hours 48hours Excipients after mixing after mixing after mixing Water forinjection (WFI) 99.42 92.43 88.85 Sodium Ascorbate, pH 5.8 99.42 95.4292.21 Dextran (60-90), 99.42 94.91 86.80 Clinical grade DTPA 99.42 95.7791.38 L-Methionine 99.42 93.39 89.58 Thiourea 99.42 94.87 89.97 L-Lysine99.42 95.45 89.52 Catechin hydrate 99.42 95.41 95.64 N-Acetyl-L-Cysteine99.42 91.19 87.41 L-Glutathione 99.42 91.18 85.56 10% EtOH 99.42 96.3592.16 Citric Acid 99.42 90.20 82.18 Salicylic Acid 99.42 93.08 87.65Sodium Bisulfite 98.61 0 N/A Lipoic Acid 98.61 92.97 87.93 D-Cysteine98.61 93.45 87.66 Phenol 98.61 94.44 87.88 Albumin 98.61 94.44 89.39

The degradation of Ac-225-DOTATATE in pure WFI was found significanteven at the most diluted concentration for bolus injection.

Example 3. Control Formulation without Excipient

The reaction mixture described in example 1 was immediately diluted to50×fold of volume with water for injection (WFI) or to 0.02 mCi/ml. pHwas tested to be 6.13. The mixture was kept at room temperature (25°C.). At different time points, purity of [²²⁵Ac]Ac-DOTA-TATE in theformulated dose were measured by radio-TLC as described in the tablebelow:

Time after Percentage of ²²⁵AC formulation present in [²²⁵Ac]Ac- (hours)DOTA-TATE Notes  0 hour 99.5% 0.5% free Actinium 24 hours 94.8% 2.0%free Actinium, 3.2% fragments 48 hours 91.8% 3.5% free Actinium, 4.8%fragments 72 hours 83.5% 8.8% free Actinium, 7.7% fragments 96 hours79.1% 9.2% free Actinium, 11.8% fragments

Example 4. Radioactivity Concentration Optimization

The reaction mixture described in example 1 was immediately diluted intoSodium Ascorbate (100 mM or 19.8 mg/ml aqueous solution, pH adjusted to5.80) aqueous solution at different concentrations; DTPA was added intothe formulation accordingly to reach the final concentration at 0.05mg/ml. The mixture was kept at room temperature (25° C.) and protectedfrom light to prevent photodegradation. At different time points, purityof [²²⁵Ac]Ac-DOTA-TATE in the formulated dose were measured by radio-TLCas described in the table below:

Percentage of ²²⁵ AC present in [²²⁵ Ac]Ac-DOTA-TATE Radioactivity 0 2448 72 96 120 concentration hour hours hours hours hours hours  15 μCi/ml99.37 96.92 96.08 98.74 94.83 93.49  32 μCi/ml 99.39 97.92 97.13 95.3192.52 85.90  68 μCi/ml 99.06 98.22 95.93 95.36 86.92 n/a 126 μCi/ml99.11 95.77 84.99 n/a n/a n/a 301 μCi/ml 99.09 97.53 88.78 n/a n/a n/a550 μCi/ml 98.87 97.04 85.63 n/a n/a n/a

Example 5. DTPA Concentration Optimization

The reaction mixture described in example 1 was immediately diluted to50×fold of volume (or to 20 μCi/ml) with Sodium Ascorbate (100 mM or19.8 mg/ml aqueous solution, pH adjusted to 5.80) aqueous solution.Different concentrations of DTPA were added. The mixture was kept atroom temperature (25° C.). At different time points, radioactivecomponents of the formulated dose were measured by radio-TLC asdescribed in the table below:

DTPA Percentage of ²²⁵AC present in [²²⁵Ac]Ac-DOTA-TATE concentration 0hour 24 hours 48 hours 72 hours 0.05 mg/ml 98.74 97.67 95.34 94.62  0.1mg/ml 97.52 98.30 96.74 94.36  0.3 mg/ml 98.06 97.19 96.11 93.60  0.5mg/ml 98.40 97.28 95.07 92.73  0.8 mg/ml 98.02 97.60 96.57 93.11  1.0mg/ml 98.25 97.37 96.14 94.14

Example 6. Sodium Ascorbate Concentration Optimization

The reaction mixture described in example 1 was immediately diluted to50×fold of volume (or to 0.02 mCi/ml) with sodium ascorbate (100 mM, pHadjusted, with 0.05 mg/ml DTPA). pH was tested to be 5.83. The mixturewas kept at room temperature (25° C.). At different time points,radioactive components of the formulated dose were measured by radio-TLCas described in the table below:

Percentage of ²²⁵ AC present in [²²⁵ Ac]Ac-DOTA-TATE Sodium ascorbate 024 48 72 96 120 144 concentration hour hours hours hours hours hourshours 200 mM  99.22 98.16 97.12 95.63 95.51 94.38 91.27 100 mM  99.1598.76 96.94 96.16 95.84 95.44 95.34  10 mM* 99.78 92.21 86.11 n/a n/an/a n/a  1 mM* 99.76 91.11 52.06 n/a n/a n/a n/a *Radioactivityconcentration at 1 mCi/ml

Example 7. Dextran Ratio Optimization

The reaction mixture described in example 1 was immediately diluted to40×fold of volume (or to 25 μCi/ml) with sodium ascorbate (100 mM, pHadjusted, with 0.05 mg/ml DTPA) in pre-mixed dextran saline solution. pHwas tested to be 5.80. The mixture was kept at room temperature (25°C.). At different time points, radioactive components of the formulateddose were measured by radio-TLC as described in the table below:

Percentage of ²²⁵ AC present in [²²⁵ Ac]Ac-DOTA-TATE Dextran 0 24 48 7296 120 144 percentage hour hours hours hours hours hours hours 10% w/w 99.67 99.02 98.75 97.83 96.42 96.58 95.37  6% w/w  100 99.08 98.83 98.2996.99 97.00 96.41  3% w/w  99.86 98.62 98.48 97.91 96.48 96.67 95.77  0%w/w  99.90 99.42 98.73 97.77 97.13 98.09* 94.64 10% w/w, 100 95.38 93.3689.11 87.20 n/a n/a no L-ascorbate * non-homogeneous sampling

Example 8. EGCg Concentration

The reaction mixture described in example 1 was immediately diluted to40×fold of volume (or to 25 μCi/ml) with sodium ascorbate (100 mM, pHadjusted 5.80, with 0.05 mg/ml DTPA) in saline solution with differentconcentration of EGCg. The mixture was kept at room temperature (25°C.). At different time points, radioactive components of the formulateddose were measured by radio-TLC as described in the table below:

Percentage of ²²⁵ AC present in [²²⁵ Ac]Ac-DOTA-TATE EGCg 0 24 48 72 96120 144 concentration hour hours hours hours hours hours hours   3 mg/ml99.81 98.57 98.00 96.55 96.42 96.05 90.71   1 mg/ml 99.76 99.14 98.8398.04 97.15 94.82 95.65 0.5 mg/ml 99.61 98.92 98.48 97.97 96.44 95.6593.04   0 mg/ml 99.90 99.42 98.73 97.77 97.13 98.09* 94.64*non-homogeneous sampling

Example 9. A Preparation of [²²⁵Ac]Ac-DOTA-TATE at a Single Patient DoseScale, its Formulation and Stability Study

For a 300 μCi (11.1 MBq) batch size, a [²²⁵Ac]Ac(NO₃)₃ solution (40 μl,11.4 MBq, assayed) was diluted with sodium acetate buffer solution (250μl, 0.4 M, pH=5.50). The DOTA-TATE acetate solution (200 μl, 1.0 mg/mlwater solution, 200 μg) was added. The mixture was mixed with vortexmixture, then heated at 90° C. for 15 min at shaking speed of 500 roundper minute on a thermal mixer. After completion, the reaction wasremoved from the mixture and allowed to cool to room temperature in 3minutes. The reaction solution was diluted with pre-mixed intravenousformulation (9.5 ml). The Actinium-225 radioactive containsconcentration was 30 mCi/L (total volume 10.0 ml). The calculated 5-daydose activity was 211 μCi (7.8 MBq, or 7.4MBq±10%). The starting molaractivity of the dose was 2.2 mCi/μmol. The formulated product wasdispensed into a 30-ml sterile vial and sealed with Wheaton's septa andcrimp seal. The vial was wrapped with aluminum foil and stored away fromlight at room temperature (about 20° C. to about 25° C.) for stabilitysampling every 24 hours. Intravenous formulation is either Formulation Aor Formulation B as described below.

Formulation A:

To prepare a 100 grams of 100 mM sodium L-ascorbate, 5% w/w Dextran 40,0.9% w/w sodium chloride saline solution, pH 5.80, 5.000 g of DEXTRAN40, 1.980 g of Sodium L-ascorbate and 5.0 mg of DTPA were dissolved in93 ml of 0.9% w/w saline. The solution container was placed on a vortexshaker and mixed for 15 minutes to completely dissolve the solid. 24 μlof HCl (conc. 12 M) was added. Final pH was measured to between5.75-5.85. The formulation solution was stored at 2-8° C. and protectedfrom exposure of light up to 12 hours before consumption.Formulation B:To prepare 250 ml of a 100 mM sodium L-ascorbate, 0.9% w/w sodiumchloride saline solution, pH 5.80, 4.950 g of Sodium L-ascorbate and12.5 mg of DTPA were dissolved in 250 ml of 0.9% w/w saline. Thesolution container was placed on a vortex shaker and mixed for 15minutes to completely dissolve the solid. 60 μl of HCl (conc. 12 M) wasadded. Final pH was measured to between 5.75-5.85. The formulationsolution was stored at 2-8° C. and protected from exposure of light upto 12 hours before consumption.

At different time points, percentage purity of [²²⁵Ac]Ac-DOTA-TATE inthe formulated dose were measured by radio-TLC as described in the tablebelow. Purity is described as the ²²⁵Ac present in [²²⁵Ac]Ac-DOTA-TATEdivided by total ²²⁵Ac content at that time point.

Percentage of ²²⁵ AC present in [²²⁵ Ac]Ac-DOTA-TATE 0 24 48 72 96 120144 168 192 Formulation hour hours hours hours hours hours hours hourshours A 98.75 98.86 98.40 98.29 96.88 96.14 95.92 94.77 94.67 B 98.4198.67 98.34 97.67 96.22 96.22 95.24 94.35 93.52

As illustrated in the table above, both Formulations A and B retain atleast 95% of the ²²⁵Ac content as ²²⁵Ac-DOTA-TATE after 120 hours and atleast 93% of the ²²⁵Ac content as ²²⁵Ac-DOTA-TATE after 192 hours.

Example 10. Preparation of [²²⁵Ac]Ac-DOTA-TATE for In VivoAdministration

[²²⁵Ac]Ac(NO₃)₃ was dissolved in 0.001M HCl to achieve a concentrationof 1 mCi in 100 μL. A 1.0-1.1 mCi aliquot of 10 μCi/μL ²²⁵Ac-chloridesolution was combined with 285 μg of 1 μg/μL DOTA-TATE solution in 0.4Msodium acetate buffer. The combined solution was brought to 2.0 mL with0.4M sodium acetate buffer and a final pH range of 6.0 to 6.5. Theradioactive concentration of the combined solution was between 0.5mCi/mL and 0.55 mCi/mL. The solution was heated and mixed with a thermalmixer at 90±3° C. for 15±2 minutes. To a separate, sterile, intermediaryvial was added 28 mL of formulation buffer (100 mM sodium ascorbate,0.05 mg/mL DTPA, 0.9% normal saline). The total contents of the combined[²²⁵Ac]Ac-DOTA-TATE solution was transferred into the intermediary vialwith the formulation buffer, further reducing the total radioactiveconcentration to 0.033-0.0367 mCi/mL in the formulation vial.

The required volume to fill to the requested patient activity dose iscalculated with appropriate decay factor to time of calibration and doserange between 146-275 μCi. If necessary, after activity has beenaliquoted to the patient vial, the vial is brought to a total volume of12 mL with formulation buffer (100 mM sodium ascorbate, 0.05 mg/mL DTPA,0.9% normal saline) for injection. Final excipient description[²²⁵Ac]Ac-DOTA-TATE for in vivo administration was formulated in asodium ascorbate concentration of 18.5±4.63 mg/mL, total DOTA-TATEpeptide concentration of ≤11.5 μg/mL, 0.05 mg/mL DTPA, 0.9% normalsaline, pH=5.5-7.0, with a dose range of 146-275 μCi at time ofcalibration in 12 mL total volume, and dose concentration at time ofcalibration between 0.012-0.023 μCi/μL. Stability up to 120 hours wasinitially verified with the bulk formulated vial and subsequently withthe dose range between 146-275 μCi.

Example 11. Preparation of ²²⁵Ac-DOTA-TATE Formulation in Unit DosageForm

The unit dosage form formulation was manufactured in a continuousprocess from radiolabeling of 225Ac into the DOTA moiety of DOTATATE, tothe final formulation with excipients. The unlabeled precursor DOTATATEwas a lyophilized powder that was reconstituted in sodium acetate bufferprior to labeling with 225Ac. DOTATATE acetate was labeled with 229Th(thorium-229)-generator-derived 225Ac under a specified temperature andreaction time to produce ²²⁵Ac-DOTATATE. After radiolabeling wascompleted, the reaction mixture was further formulated in a buffer withselected excipients deemed necessary to mitigate radiolysis andbreakdown of the drug product:

18.5 mg/mL L-sodium ascorbate (e.g., to mitigate radiolysis of theradiopharmaceutical preparation and extend stability)

0.05 mg/mL diethylenetriamine pentaacetate (e.g., to scavenge freeunbound 225Ac)

0.9% normal saline (to further dilute to a total infusion volume of 12mL)

Other suitable excipients may also be used.

Example 12. Clinical Trial Design and Dosing Schedule

The clinical trial design is a Phase 1b/Phase 3 global, multicenter,randomized, controlled, open-label trial comparing treatment with[²²⁵Ac]Ac-DOTA-TATE to standard of care therapy in subjects withinoperable, advanced, Grade 1-2, well-differentiated, somatostatinreceptor positive (SSTR+) GEP-NETs that have progressed according toRECIST v.1.1 following prior treatment with ¹⁷⁷Lu-DOTA-TATE or¹⁷⁷Lu-DOTA-TOC.

Part 1 of the study is to determine the recommended Phase 3 dose (RP3D),with dose de-escalation/re-escalation rules based on the Bayesianoptimal interval (BOIN) design (Liu and Yuan 2015; Yuan 2016). Sixsubjects are planned to be enrolled in 3 dose cohorts for a total of 18subjects if all 3 dose levels are initiated. A cohort may be expandede.g., to a maximum of 10 subjects. The starting dose of[²²⁵Ac]Ac-DOTA-TATE will be 120 kBq/kg (3.2 μCi/kg). Subjects willreceive up to 4 cycles of [²²⁵Ac]Ac-DOTA-TATE every 8 weeks. Dosede-escalation (between cohorts) and potential re-escalation will bedecided by the DRC based on the dose limiting toxicity rate observedduring the first 56 days following the first administration of[²²⁵Ac]Ac-DOTA-TATE. Concomitant IV amino acids (solution containingL-arginine and L-lysine) will be given with each [²²⁵Ac]Ac-DOTA-TATEadministration for renal protection, starting 30 minutes before the[²²⁵Ac]Ac-DOTA-TATE infusion and continuing for a total of 4 hours.

A representative dosing scheme for Part I is illustrated in FIG. 19 .

The Eligibility Criteria of the Part I study can include one or more ofthe following:

Age≥18

Histologically proven, G1-3 well-differentiated GEP-NETs

Ki-67≤55%

Progressive GEP-NET based on RECIST v.1.1 (centrally confirmed)following 177Lu-DOTATATE or 177Lu-DOTATOC

RECIST v1.1 measurable SSTR+ disease within 4 weeks prior to dose(centrally confirmed; no SSTR-neg metastatic disease)

CrCl≥50 mL/min

Subjects with p-NET have also received an additional non-SSAantineoplastic agent in addition to prior PRRT

The end point of the Part I study can include one or more of thefollowing:

Primary: Dose Limiting Toxicities (DLTs)

Secondary/exploratory:

Recommended Phase 2 dose (RP2D)

Safety

objective response rate (ORR)

PK

Part 2 (randomized, controlled Phase 3) is to determine if treatmentwith [²²⁵Ac]Ac-DOTA-TATE prolongs progression free survival as assessedby blinded independent central review (BICR) (primary objective) and OS(key secondary objective) compared with standard of care therapy. Atotal of 210 subjects are planned for randomization at a 1:1 ratio toreceive [²²⁵Ac]Ac-DOTA-TATE administered at the RP3D every 8 weeks forup to 4 cycles or standard of care therapy selected by the Investigatorprior to randomization and given according to local labeling (standardof care options may include oral everolimus, oral sunitinib, high doseoctreotide long-acting release (LAR), and high dose lanreotide).Following radiographic progressive disease confirmed by BICR, subjectsrandomized to the standard of care therapy group may be eligible tocross over and receive [²²⁵Ac]Ac-DOTA-TATE. Pharmacokinetic evaluationsof [²²⁵Ac]Ac-DOTA-TATE in blood and urine will be completed in Part 1 ofthe study (all subjects) and in a subset of subjects randomized to[²²⁵Ac]Ac-DOTA-TATE in Part 2 of the study. In addition, a PK/ECGsubstudy will be conducted in a subset of subjects randomized to[²²⁵Ac]Ac-DOTA-TATE during Part 2.

The Eligibility Criteria of the Part 2 study can include one or more ofthe following:

Age≥18

Histologically proven, well-differentiated, G1-2 GEP-NETs

Ki-67≤20%

Progressive GEP-NET based on RECIST v.1.1 (centrally confirmed)following 177Lu-DOTATATE or 177Lu-DOTATOC

RECIST v1.1 measurable SSTR+ disease within 4 weeks prior to dose(centrally confirmed; no RECIST measurable SSTR-neg metastatic disease)

ECOG≤2

CrCl≥50 mL/min

The end point of the Part 2 study can include one or more of thefollowing:

Primary: blinded independent central review (BICR) progression-freesurvival (PFS)

Secondary/exploratory:

overall survival (OS)

objective response rate (ORR)

duration of Response

Disease Control Rate

Safety

PK

Biomarkers

QOL

Example 13: Preparation of [²²⁵Ac]Ac-DOTA-TATE at a 1 mCi Batch Size,its Formulation and Stability Study

For a 1 mCi (37 MBq) batch size, a [²²⁵Ac]Ac(NO₃)₃ solution (93 μL, 995μCi assayed) was diluted with sodium acetate buffer solution (1401 μl,0.4M, pH=5.53). The DOTA-TATE acetate solution (285 μg, 0.964 μg/μLsodium acetate buffer, 296 μL) was added for a molar activity of 5.009Ci/mmol. The target reaction radioactive concentration was 0.556 μCi/μLwith a total reaction volume of 1,789 μL. The mixture was mixed with avortexer, then heated at 90° C. for 15 minutes at shaking speed of 500rounds per minute on a thermal mixer. After completion, the reactionvial was removed from the thermal mixer and cooled to room temperature(about 20° C. to about 25° C.) in 3 minutes. The entire reaction mixturewas then added to 28.2 mL of a pre-mixed formulation buffer (FormulationB) consisting of 100 mM sodium L-ascorbate, 0.05 mg/mL DTPA in 0.9%saline (pH=5.79). The final assay of the bulk vial solution was 984 μCiin a total volume of 30,000 μL, for a final product radioactiveconcentration of 0.033 μCi/μL and final pH of 5.67. A total of 3aliquots from the bulk vial was distributed to 3 separate vials,simulating patient dose activity levels of 307.5 μCi in 9 mL, 309.5 μCiin 9 mL, and 310 μCi in 9 mL. Each of the simulated patient vial wasprotected from light and stored in room temperature (20-25° C.).Stability sampling was taken every 24 hours from the 309.5 μCi vial,with an end specification of ≥95% by t=120 hours from end of synthesis.

At different time points, percentage purity of [²²⁵Ac]Ac-DOTA-TATE inthe formulated dose were measured by radio-TLC as described in the tablebelow. Purity is described as the ²²⁵Ac present in [²²⁵Ac]Ac-DOTA-TATEdivided by total ²²⁵Ac content at that time point.

Percentage of ²²⁵ AC present in [²²⁵ Ac]Ac-DOTA-TATE 0 24 48 72 96 120144 hour hours hours hours hours hours hours 1 mCi 99.21% 98.87% 97.21%96.54% Not 95.52% 94.81% Formulation measured

As illustrated in the table above, the formulation of Example 13 retainsat least 95% of the ²²⁵Ac content as ²²⁵Ac-DOTA-TATE after 120 hours.

Example 14: [²²⁵Ac]Ac-DOTA-TATE Dosing Calculation Based on PatientWeight

An 85 kg patient is treated with a dose of 3.24 μCi/kg (120 kBq/kg)[²²⁵Ac]Ac-DOTA-TATE representing a total radiation dose of 275 μCi(10,200 kBq) at time of injection. The final product after synthesis andformulation has a radioactive concentration of 0.033 μCi/μL. Given thehalf-life of ²²⁵Ac, the dose is formulated to contain a certain amountof radioactivity dependent upon when the dose will be administeredaccording to the following table:

Days before administration 1 2 3 4 5 μCi in 295 317 340 364 391radiopharmaceutical Volume of 8.9 9.6 10.3 11.0 11.8 radiopharmaceutical(mL)The dose is then brought up to 12 mL total volume with formulationbuffer for administration. Patients less than 85 kg receive the same3.24 μCi/kg (120 kBq/kg) dose of [²²⁵Ac]Ac-DOTA-TATE brought up to 12 mLtotal volume with formulation buffer for administration.

Further, the table below summaries the dose calculation for patientshaving different weights at a dose of 120 kBq/kg:

Patent weight (kg) 40 45 50 55 60 65 70 75 80 85 Dose at time of 130 146162 178 194 211 227 243 259 275 injection (in μCi) Dose at time of 48005400 6000 6600 7200 7800 8400 9000 9600 10200 injection (in kBq) Daysbefore administration Activity needed (in μC) at day of manufacture ifinjected x days later 1 139 156 174 191 208 226 243 261 278 295 2 149168 186 205 224 242 261 279 298 317 3 160 180 200 220 240 260 280 300320 340 4 171 193 214 236 257 278 300 321 343 364 5 184 207 230 253 276299 322 345 368 391 Days before administration Volume needed (in mL) ifbulk drug product concentration = 0.033 μCi/μL 1 4.2 4.7 5.3 5.8 6.3 6.87.4 7.9 8.4 8.9 2 4.5 5.1 5.6 6.2 6.8 7.3 7.9 8.5 9.0 9.6 3 4.8 5.4 6.16.7 7.3 7.9 8.5 9.1 9.7 10.3 4 5.2 5.8 6.5 7.1 7.8 8.4 9.1 9.7 10.4 11.05 5.6 6.3 7.0 7.7 8.4 9.0 9.7 10.4 11.1 11.8

Disclosure of the present application is further illustrated in thefollowing list of embodiments, which are given for illustration purposesonly and are not intended to limit the disclosure in any way:

Embodiment 1: A liquid radiopharmaceutical composition comprising:

-   -   a. a conjugate, wherein the conjugate is ²²⁵Ac-DOTA-TATE;    -   b. one or more stabilizing agents; and    -   c. an aqueous vehicle.        Embodiment 2: A liquid radiopharmaceutical composition        comprising:    -   d. a conjugate, wherein the conjugate is ²²⁵Ac-DOTA-TOC;    -   e. one or more stabilizing agents; and    -   f. an aqueous vehicle.        Embodiment 3: A liquid radiopharmaceutical composition        comprising:    -   a) a conjugate that comprises        -   i. a targeting ligand,        -   ii. a metal chelator covalently attached to the targeting            ligand, and        -   iii. a radionuclide, wherein the radionuclide is bound to            the metal chelator;    -   b) one or more stabilizing agents; and    -   c) an aqueous vehicle.        Embodiment 4: The radiopharmaceutical composition of Embodiment        3, wherein the targeting ligand binds to a somatostatin receptor        (SSR).        Embodiment 5: The radiopharmaceutical composition of Embodiment        4, wherein the targeting ligand binds to a somatostatin receptor        type 1 (SSTR1), somatostatin receptor type 2 (SSTR2),        somatostatin receptor type 3 (SSTR3), somatostatin receptor type        4 (SSTR4), and/or somatostatin receptor type 5 (SSTR5).        Embodiment 6: The radiopharmaceutical composition of Embodiment        4, wherein the targeting ligand binds to a somatostatin receptor        type 2 (SSTR2).        Embodiment 7: The radiopharmaceutical composition of Embodiments        3 to 6, wherein the targeting ligand is a binding peptide.        Embodiment 8: The radiopharmaceutical composition of Embodiment        7, wherein the binding peptide comprises 6 to 14 amino acid        residues.        Embodiment 9: The radiopharmaceutical composition of Embodiment        7 or 8, wherein the binding peptide comprises an amino acid        sequence with at least 90% identity to a sequence selected from        SEQ IDs 1 to 96.        Embodiment 10: The radiopharmaceutical composition of Embodiment        7 or 8, wherein the binding peptide comprises an amino acid        sequence selected from SEQ IDs 1 to 96.        Embodiment 11: The radiopharmaceutical composition of Embodiment        3 to 6, wherein the targeting ligand is octreotate, octreotide,        D-Phe¹-cyclo(Cys²-Tyr³-D-Trp⁴-Lys⁵-Thr⁶-Cys⁷)Thr⁸ (SEQ ID        NO: 97) (tyr³-octreotate or TATE),        D-Phe¹-cyclo(Cys²-Tyr³-D-Trp⁴-Lys⁵-Thr⁶-Cys⁷)Thr(ol)⁸ (SEQ ID        NO: 98) (Phe¹-Tyr³octreotide, edotreotide, or TOC),        D-Phe¹-cyclo(Cys²-Phe³-D-Trp⁴-Lys⁵-Thr⁶-Cys⁷)Thr(ol)⁸ (SEQ ID        NO: 99) (OC),        D-Phe¹-cyclo(Cys²-1-Nal-D-Trp⁴-Lys⁵-Thr⁶-Cys⁷)Thr(ol)⁸ (SEQ ID        NO: 100) (NOC),        p-Cl-Phe-cyclo(D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys)D-Tyr-NH₂)        (SEQ ID NO: 101) (JR11), or        p-Cl-Phe-cyclo(D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys)-D-Tyr-NH₂ (SEQ        ID NO: 102) (LM3).        Embodiment 12: The radiopharmaceutical composition of Embodiment        3 to 6, wherein the targeting ligand is tyr³-octreotate,        edotreotide, octreotate, or octreotide.        Embodiment 13: The radiopharmaceutical composition of Embodiment        3 to 6, wherein the targeting ligand is tyr³-octreotate.        Embodiment 14: The radiopharmaceutical composition of        Embodiments 4 to 13, wherein targeting ligand is an agonist of        the SSR.        Embodiment 15: The radiopharmaceutical composition of        Embodiments 4 to 13, wherein targeting ligand is an antagonist        of the SSR.        Embodiment 16: The radiopharmaceutical composition of        Embodiments 3 to 6, wherein the targeting ligand is a small        molecule compound.        Embodiment 17: The radiopharmaceutical composition of Embodiment        16, wherein the small molecule compound is L-797,591, L-779,976,        L-796,778, L-803,087, or L-817,818.        Embodiment 18: The radiopharmaceutical composition of        Embodiments 4 to 17, wherein a binding affinity of the targeting        ligand to a human SSR is not more than 250 nM, as determined by        half maximal inhibitory concentration (IC₅₀).        Embodiment 19: The radiopharmaceutical composition of        Embodiments 4 to 18, wherein the binding affinity of the        targeting ligand to a human SSR is not more than 100 nM, as        determined by half maximal inhibitory concentration (IC₅₀).        Embodiment 20: The radiopharmaceutical composition of        Embodiments 4 to 19, wherein the binding affinity of the        targeting ligand to a human SSR is not more than 50 nM, as        determined by half maximal inhibitory concentration (IC₅₀).        Embodiment 21: The radiopharmaceutical composition of        Embodiments 4 to 20, wherein the binding affinity of the        targeting ligand to a human SSR is not more than 5 nM, as        determined by half maximal inhibitory concentration (IC₅₀).        Embodiment 22: The radiopharmaceutical composition of        Embodiments 4 to 21, wherein the binding affinity of the        targeting ligand to a human SSR is not more than 2 nM, as        determined by half maximal inhibitory concentration (IC₅₀).        Embodiment 23: The radiopharmaceutical composition of        Embodiments 18 to 22, wherein the human SSR is SSTR2.        Embodiment 24: The radiopharmaceutical composition of        Embodiments 3 to 23, wherein the targeting ligand is covalently        linked to the metal chelator through a linker.        Embodiment 25: The radiopharmaceutical composition of        Embodiments 3 to 24, wherein the metal chelator is selected from        AAZTA, BAT, BAT-TM, Crown, Cyclen, DO2A, CB-DO2A, DO3A,        H3HP-DO3A, Oxo-DO3A, p-NH₂-Bn-Oxo-DO3A, DOTA, DOTA-3py, DOTA-PA,        DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-1py, p-SCN-Bn-DOTA,        CHX-A″-EDTA, MeO-DOTA-NCS EDTA, DOTAMAP, DOTAGA,        DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB-Cyclam, TE2A,        CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, NOTA, NOTP, HEHA, HEHA-NCS,        p-SCN-Bn-HEHA, DTPA, CHX-A″-DTPA, p-NH₂-Bn-CHX-A″-DTPA,        p-SCN-DTPA, p-SCN-Bz-Mx-DTPA, 1B4M-DTPA-DTPA, p-SCN-Bn1B-DTPA,        p-SCN-Bn-1B4M-DTPA, p-SCN-Bn-CHX-A″-DTPA, PEPA, p-SCN-Bn-PEPA,        TETPA, DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene-tetracarboxylic        acid, macropa, macropa-NCS, macropid, H₃L¹, H₃L⁴, H₂azapa,        H₅decapa, bispa², H₄pypa, H₄octapa, H₄CHXoctapa,        p-SCN-Bn-H₄octapa, p-SCN-Bn-H₄octapa, TTHA, p-NO₂-Bn-neunpa,        H₄octox, H₂macropa, H₂bispa², H₄phospa, H₆phospa,        p-SCN-Bn-H₆phospa, TETA, p-NO₂-Bn-TETA, TRAP, TRAP-Pr, TPA,        HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, lipoic        acid, TGA, BAL, Bis-thioseminarabazones, p-SCN-NOTA, nNOTA,        NODAGA, CB-TE1A1P, 3P-C-NETA-NCS, 3p-C-DEPA, 3P-C-DEPA-NCS,        TCMC, PCTA, NODIA-Me, TACN, pycuplAiB, pycup2A, THP, DEDPA,        H₂DEDPA, p-SCN-Bn-H₂DEDPA, p-SCN-Bn-TCMC, motexafin, NTA, NOC,        3p-C-NETA, p-NH₂-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar,        BaBaSar, TACN-TM, CP256, C-NE3TA, C-NE3TA-NCS, NODASA,        NETA-monoamide, C-NETA, TACN-HSB, NOPO, BPCA, p-SCN-Bn-DRO,        DRO-ChX-Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD, BAPEN,        TACHPYR, NEC-SP, L^(PY), L1, L2, L3, and EuK-106.        Embodiment 26: The radiopharmaceutical composition of        Embodiments 3 to 24, wherein the metal chelator is a metal        chelator in FIG. 3 to FIG. 17 .        Embodiment 27: The radiopharmaceutical composition of        Embodiments 3 to 26, wherein the metal chelator is DOTA, HEHA,        or macropa.        Embodiment 28: The radiopharmaceutical composition of        Embodiments 3 to 27, wherein the metal chelator is DOTA.        Embodiment 29: The radiopharmaceutical composition of        Embodiments 1 to 28, wherein the one or more stabilizing agents        comprise a radiolysis stabilizer.        Embodiment 30: The radiopharmaceutical composition of Embodiment        29, wherein the radiolysis stabilizer is

a) an amino acid or a peptide or a derivative thereof,

b) a vitamin or a derivative thereof,

c) a lipid or a derivative thereof,

d) a carbohydrate or a derivative thereof,

e) a volume expander or

f) an antioxidant.

Embodiment 31: The radiopharmaceutical composition of Embodiment 30,wherein the amino acid or peptide is selected from N-Acetyl-L-cysteine,Glutathione, L-Lysine, Selenol-L-methionine, Glutathione, Albumin,Melatonin, Taurine, Alanine, Arginine, Asparagine, Aspartic acid,Cysteine, Glutamine, Glutamic acid, Glycine, Histidine, Isoleucine,Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine,Tryptophan, Tyrosine, Valine, and derivatives thereof.Embodiment 32: The radiopharmaceutical composition of Embodiment 31,wherein the amino acid is Methionine.Embodiment 33: The radiopharmaceutical composition of Embodiment 30,wherein the radiolysis stabilizer is an antioxidant.Embodiment 34: The radiopharmaceutical composition of Embodiment 33,wherein the antioxidant is a flavonoid or a derivative thereof.Embodiment 35: The radiopharmaceutical composition of Embodiment 34,wherein the flavonoid is(2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol3-(3,4,5-trihydroxybenzoate ((−) Catechin gallate or CG),3,3′,4′,5,5′,7-Hexahydroxyflavylium chloride,(−)-cis-3,3′,4′,5,7-Pentahydroxyflavane (Epi-Catechin or EC),7-Hydroxy-3-(4′-methoxyphenyl)-4H-benzopyran-4-one,3,4,5-Trihydroxybenzoic acid (Gallic acid), 3,4′,5,7-Tetrahydroxyflavone(Kaempferol), Luteolin,2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethylloxan-2-yl]oxychromen-4-one(Rutin hydrate), Quercetin,(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl3,4,5-trihydroxybenzoate (EpiGallo-Catechin gallate or EGCg),(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoateor Epi-Catechin Gallate (ECG),(2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Epigallo-Catechin or EGC), or(2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Gallo-Catechin or GC).Embodiment 36: The radiopharmaceutical composition of Embodiment 34,wherein the flavonoid is a catechin or a derivative thereof.Embodiment 37: The radiopharmaceutical composition of Embodiment 36,wherein the catechin or catechin derivative is(2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol3-(3,4,5-trihydroxybenzoate ((−) Catechin gallate or CG),(−)-cis-3,3′,4′,5,7-Pentahydroxyflavane (Epi-Catechin or EC),3,4,5-Trihydroxybenzoic acid (Gallic acid),(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl3,4,5-trihydroxybenzoate (EpiGallo-Catechin gallate or EGCg),(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoateor Epi-Catechin Gallate (ECG),(2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Epigallo-Catechin or EGC), or(2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Gallo-Catechin or GC).Embodiment 38: The radiopharmaceutical composition of Embodiment 33,wherein the antioxidant is a carotenoid or a derivative thereof.Embodiment 39: The radiopharmaceutical composition of Embodiment 38,wherein the carotenoid is all-trans-Fucoxanthin, Lycopene, Xanthophyll,Beta carotene, Lycopene, or Lutein.Embodiment 40: The radiopharmaceutical composition of Embodiment 33,wherein the antioxidant is N-acetyl cysteine, L-Ascorbic acid,N-tert-Butyl-α-phenylnitrone, 3-(3,4-Dihydroxyphenyl)-2-propenoic acid(Caffeic Acid), β-Carotene, Provitamin A,(2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol3-(3,4,5-trihydroxybenzoate ((−) Catechin gallate or CG),1,4,5-Trihydroxycyclohexanecarboxylic acid, trans-4-Hydroxycinnamic acid(p-Coumaric acid), 3,3′,4′,5,5′,7-Hexahydroxyflavylium chloride,Thiocytic Acid (Dihydrolipoic Acid, DHLA),4,4′,5,5′,6,6′-Hexahydroxydiphenic acid 2,6,2′,6′-dilactone (Ellagicacid), (−)-cis-3,3′,4′,5,7-Pentahydroxyflavane (Epi-Catechin or EC),2-Methoxy-4-(2-propenyl) phenol, trans-4-Hydroxy-3-methoxycinnamic acid(Ferulic acid), 7-Hydroxy-3-(4′-methoxyphenyl)-4H-benzopyran-4-one,all-trans-Fucoxanthin, 3,4,5-Trihydroxybenzoic acid (Gallic acid),(2S,3R)-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol((−)-Gallocatechin), Glutathione, 2-(3,4-Dihydroxyphenyl)ethanol,3,4′,5,7-Tetrahydroxyflavone (Kaempferol),(±)-1,2-Dithiolane-3-pentanoic acid, Luteolin, Lycopene, L-Lysine,Neochlorogenic acid, Oleic acid, trans-3,5,4′-Trihydroxystilbene(Resveratrol),2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one,Rutin hydrate, Selenol-L-methionine, Thiourea, (+)-α-Tocopherol,Xanthophyll, Citric acid (CA), Gentisic acid (GA), Salicylic acid (SA),Erythorbic acid (EA), Phenol, Sodium bisulfite, Butylated hydroxyanisole, Butylated hydroxy toluene, Metabisulfite, Benzyl alcohol,Thymol, Lipoic acid (LA), Thioglycolic acid (TGA), 2,3Dimercaptopropan-1-ol (BAL), Zinc, Selenium, Albumin, Ethanol, Mannitol,Sucrose, Melatonin, Ebselen, Pyruvic acid, Carboxy-PTIO, Trolox, Uricacid, Edaravone, Beta carotene, NADPH, Lycopene, Lutein, Catalase,Estrogen, Estradiol, Estriol, Ubiquinol, Copper, Quercetin, Cortisone,Taurine,(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl3,4,5-trihydroxybenzoate (EpiGallo-Catechin gallate or EGCg),(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoate or Epi-Catechin Gallate (ECG),(2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Epigallo-Catechin or EGC),(2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Gallo-Catechin or GC),(−)-cis-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol3-gallate ((−)-Epigalocatechin-3-O-Gallate), 5-Aminolevulibic Acidhydrate, Ploysorbate 80, Garlic Acid, Sodium L-Ascorbate, HyaluronicAcid, Dextran 60-90, Selenol, and LysaKare.Embodiment 41: The radiopharmaceutical composition of Embodiment 30,wherein the radiolysis stabilizer is a vitamin or a derivative thereof.Embodiment 42: The radiopharmaceutical composition of Embodiment 41,wherein the vitamin or a derivative thereof is selected from L-Ascorbicacid, β-Carotene, Provitamin A, (+)-α-Tocopherol, Erythorbic acid (EA),Trolox, and Lutein.Embodiment 43: The radiopharmaceutical composition of Embodiment 30,wherein the radiolysis stabilizer is a lipid.Embodiment 44: The radiopharmaceutical composition of Embodiment 43,wherein the lipid is a fatty acid.Embodiment 45: The radiopharmaceutical composition of Embodiment 44,wherein the fatty acid is a saturated or unsaturated C₆ to C₃₀ fattyacid.Embodiment 46: The radiopharmaceutical composition of Embodiment 45,wherein the fatty acid is oleic acid, Myristoleic acid, Palmitoleicacid, Sapienic acid, Elaidic acid, Vaccenic acid, or Linoleic acid,α-Linolenic acid.Embodiment 47: The radiopharmaceutical composition of Embodiment 43,wherein the lipid is a steroid or derivatives thereof.Embodiment 48: The radiopharmaceutical composition of Embodiment 47,wherein the steroid is Estrogen, Estradiol, Estriol, or Cortisone.Embodiment 49: The radiopharmaceutical composition of Embodiment 30,wherein the radiolysis stabilizer is a carbohydrate or a derivativethereof.Embodiment 50: The radiopharmaceutical composition of Embodiment 49,wherein the carbohydrate is Mannitol, Sucrose, Dextran (e.g., Dextran40, Dextran 70), or Cyclodextrin (e.g., α-cyclodextrin, β-cyclodextrin,and γ-cyclodextrin).Embodiment 51: The radiopharmaceutical composition of Embodiment 30,wherein the radiolysis stabilizer is a volume expander.Embodiment 52: The radiopharmaceutical composition of Embodiment 51,wherein the volume expander is a polymer or a polymer mixture.Embodiment 53: The radiopharmaceutical composition of Embodiment 52,wherein the polymer or the polymer mixture comprises PEG (e.g., Mn 2000to 5000), Polygeline, Haemaccel, Gelofusine, PLENVU (polyethylene glycol3350, sodium sulfate, ascorbic acid, sodium chloride and potassiumchloride US FDA 2018 Label), or a combination thereof.Embodiment 54: The radiopharmaceutical composition of Embodiment 51,wherein the volume expander is selected from Dextran (e.g., Dextran 40,Dextran 70), Cyclodextrins (e.g., α-cyclodextrin, β-cyclodextrin, andγ-cyclodextrin), PEG, Polygeline, Gelofusine, and PLENVU.Embodiment 55: The radiopharmaceutical composition of Embodiment 29,wherein the radiolysis stabilizer is selected from N-Acetyl-L-cysteine,L-Ascorbic acid, N-tert-Butyl-α-phenylnitrone,3-(3,4-Dihydroxyphenyl)-2-propenoic acid (Caffeic Acid), β-Carotene,Provitamin A,(2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol3-(3,4,5-trihydroxybenzoate ((−) Catechin gallate, or CG),1,4,5-Trihydroxycyclohexanecarboxylic acid, trans-4-Hydroxycinnamic acid(p-Coumaric acid), 3,3′,4′,5,5′,7-Hexahydroxyflavylium chloride,Thiocytic Acid (Dihydrolipoic Acid, DHLA),4,4′,5,5′,6,6′-Hexahydroxydiphenic acid 2,6,2′,6′-dilactone (Ellagicacid), (−)-cis-3,3′,4′,5,7-Pentahydroxyflavane (Epi-Catechin or EC),2-Methoxy-4-(2-propenyl) phenol, trans-4-Hydroxy-3-methoxy cinnamic acid(Ferulic acid), 7-Hydroxy-3-(4′-methoxyphenyl)-4H-benzopyran-4-one,all-trans-Fucoxanthin, 3,4,5-Trihydroxybenzoic acid (Gallic acid),(2S,3R)-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol((−)-Gallocatechin), Glutathione, 2-(3,4-Dihydroxyphenyl)ethanol,3,4′,5,7-Tetrahydroxyflavone (Kaempferol),(±)-1,2-Dithiolane-3-pentanoic acid, Luteolin, Lycopene, L-Lysine,Neochlorogenic acid, Oleic acid, trans-3,5,4′-Trihydroxystilbene(Resveratrol),2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one,Rutin hydrate, Selenol-L-methionine, Thiourea, (+)-α-Tocopherol,Xanthophyll, Alanine and its derivatives, Arginine and its derivatives,Asparagine and its derivatives, Aspartic acid and its derivatives,Cysteine and its derivatives, Glutamine and its derivatives, Glutamicacid and its derivatives, Glycine and its derivatives, Histidine and itsderivatives, Isoleucine and its derivatives, Lysine and its derivatives,Methionine and its derivatives, Phenylalanine and its derivatives,Proline and its derivatives, Serine and its derivatives, Threonine andits derivatives, Tryptophan and its derivatives, Tyrosine and itsderivatives, Valine and its derivatives, Citric acid (CA), Gentisic acid(GA), Salicylic acid (SA), Erythorbic acid (EA), Phenol, Sodiumbisulfite, Butylated hydroxy anisole, Butylated hydroxy toluene,Glutathione, Metabisulfite, Benzyl alcohol, Thymol, Lipoic acid (LA),Thioglycolic acid (TGA), 2,3 Dimercaptopropan-1-ol (BAL), Zinc,Selenium, Albumin, Ethanol, Mannitol, Sucrose, Melatonin, Ebselen,Pyruvic acid, Carboxy-PTIO, Trolox, Uric acid, Edaravone, Beta carotene,NADPH, Lycopene, Lutein, Catalase, Estrogen, Estradiol, Estriol,Ubiquinol, Copper, Quercetin, Cortisone, 2,3-dimercaptosuccinic acid(DMSA), monisoamyl derivative (MiADMSA), Taurine, Dextran (e.g., Dextran40, Dextran 70), PEG (e.g., PEG 3350 and PEG 4000), Polygeline,Gelofusine, PLENVU (polyethylene glycol 3350, sodium sulfate, ascorbicacid, sodium chloride and potassium chloride US FDA 2018 Label),Cyclodextrins (e.g., α-cyclodextrin, β-cyclodextrin, andγ-cyclodextrin),(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl3,4,5-trihydroxybenzoate (EpiGallo-Catechin gallate or EGCg),(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoate or Epi-Catechin Gallate (ECG),(2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Epigallo-Catechin or EGC),(2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol(Gallo-Catechin or GC).Embodiment 56: The radiopharmaceutical composition of Embodiments 29 to55, wherein the one or more stabilizing agents comprise a first and asecond radiolysis stabilizer.Embodiment 57: The radiopharmaceutical composition of Embodiment 56,wherein a molar ratio of the first and the second radiolysis stabilizeris from 1:1000 to 1:1000, 1:100 to 1:100 or 1:20 to 20:1.Embodiment 58: The radiopharmaceutical composition of Embodiment 56,wherein a molar ratio of the first and the second radiolysis stabilizeris from 1:5 to 5:1.Embodiment 59: The radiopharmaceutical composition of Embodiments 29 to58, wherein the radiolysis stabilizer is present in theradiopharmaceutical composition at about 0.01 mM to about 5 M.Embodiment 60: The radiopharmaceutical composition of Embodiment 59,wherein the stabilizing agent is present in the radiopharmaceuticalcomposition from about 5 mM, 10 mM, 25 mM, 50 mM, or 75 mM to about 80mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 250 mM, or 500 mM.Embodiment 61: The radiopharmaceutical composition of Embodiment 59,wherein the stabilizing agent is present in the radiopharmaceuticalcomposition at about 0.1 mM to about 500 mM.Embodiment 62: The radiopharmaceutical composition of Embodiment 59,wherein the stabilizing agent is present in the radiopharmaceuticalcomposition at about 10 mM to about 500 mM.Embodiment 63: The radiopharmaceutical composition of Embodiment 59,wherein the stabilizing agent is present in the radiopharmaceuticalcomposition at about 20 mM to about 100 mM.Embodiment 64: The radiopharmaceutical composition of Embodiments 29 to58, wherein the radiolysis stabilizer is present in theradiopharmaceutical composition at about 0.0001 wt % to about 10 wt %.Embodiment 65: The radiopharmaceutical composition of Embodiment 64,wherein the radiolysis stabilizer is present in the radiopharmaceuticalcomposition at about 0.01 wt % to about 5 wt %, about 0.05 wt % to about2 wt %, or about 0.1 wt % to about 1 wt %.Embodiment 66: The radiopharmaceutical composition of Embodiments 29 to58, wherein the radiolysis stabilizer is present in theradiopharmaceutical composition at a concentration of from about 0.1 to50 mg/mL.Embodiment 67: The radiopharmaceutical composition of Embodiments 30 to58, wherein the volume expander is present in the radiopharmaceuticalcomposition at a concentration of from about 0.001 wt % to 80% wt %.Embodiment 68: The radiopharmaceutical composition of Embodiments 1 to66, wherein the one or more stabilizing agents comprise a free metalchelator, wherein the free metal chelator is not attached to thetargeting ligand.Embodiment 69: The radiopharmaceutical composition of Embodiment 67,wherein the free metal chelator is selected fromEthylenediaminetetraacetic acid (EDTA), Diethylenetriaminepentaaceticacid (DTPA),2-S-(4-Isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triaceticacid (NOTA), Triethylenetetramine (TETA), 1, 4, 7, 10,13-pentaazacyclopentadecane-N, N′, N″, N′″, N″″-pentaacetic acid (PEPA),TETPA,2,2′,2″-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triaceticacid (DOTA-GA), 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid (DOTP), Deferoxamine (DFO), N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED),1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid)(DOTP),6,6′-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinicacid (Macropa), Meso-2,3-dimercaptosuccinic acid (DMSA),Dimercaptopropane sulfonate (DMPS), Dihydrolipoic acid (DHLA), Lipoicacid (LA), Thioglycolic acid (TGA), 2,3 Dimercaptopropan-1-ol (BAL).Embodiment 70: The radiopharmaceutical composition of Embodiment 69,wherein the free metal chelator is EDTA, DTPA, or Macropa.Embodiment 71: The radiopharmaceutical composition of Embodiments 67 to70, wherein the free metal chelator is present in theradiopharmaceutical composition at about 0.001 wt % to about 10 wt %.Embodiment 72: The radiopharmaceutical composition of Embodiment 71,wherein the free metal chelator is present in the radiopharmaceuticalcomposition at about 0.01 wt % to about 5 wt %, about 0.05 wt % to about2 wt %, or about 0.1 wt % to about 1 wt %.Embodiment 73: The radiopharmaceutical composition of Embodiments 67 to70, wherein the free metal chelator is present in theradiopharmaceutical composition at a concentration of from 0.01 to 50mg/mL.Embodiment 74: The radiopharmaceutical composition of Embodiments 67 to70, wherein the free metal chelator is present in theradiopharmaceutical composition at about 10 mM to about 500 mM.Embodiment 75: The radiopharmaceutical composition of Embodiments 67 to70, wherein the free metal chelator is present in theradiopharmaceutical composition at about 5 mM to 10 mM, 10 mM to 25 mM,25 mM to 50 mM, 50 mM to 75 mM, 75 mM to 100 mM, or 100 mM to 200 mM.Embodiment 76: The radiopharmaceutical composition of Embodiments 1 to75, wherein the one or more stabilizing agents comprise one or more pHstabilizers.Embodiment 77: The radiopharmaceutical composition of Embodiment 76,wherein the one or more pH stabilizers function as a pH buffer.Embodiment 78: The radiopharmaceutical composition of Embodiments 76 or77, wherein the one or more pH stabilizers comprise an organic acid.Embodiment 79: The radiopharmaceutical composition of Embodiment 78,wherein the organic acid is an acetic acid, fumaric acid, ascorbic acid,propionic acid, benzene sulfonic acid, carbonic acid, citrate acid,aspartic acid, maleic acid, methane sulfonic acid, or tartaric acid.Embodiment 80: The radiopharmaceutical composition of Embodiments 76 to79, wherein the one or more pH stabilizers comprise an inorganic acid.Embodiment 81: The radiopharmaceutical composition of Embodiment 80,wherein the inorganic acid is hydrobromic acid, hydrochloric acid,phosphoric acid, boric acid, or sulfuric acid.Embodiment 82: The radiopharmaceutical composition of Embodiments 76 to81, wherein the one or more pH stabilizers comprise a base.Embodiment 83: The radiopharmaceutical composition of Embodiment 82,wherein the base is tromethamine (Tris), ammonium hydroxide,diethanolamine, or sodium hydroxide.Embodiment 84: The radiopharmaceutical composition of Embodiments 76 to83, wherein the one or more pH stabilizers comprise an amino acid or asalt thereof.Embodiment 85: The radiopharmaceutical composition of Embodiment 84,wherein the amino acid is glycine, lysine, arginine, histidine, or asalt thereof.Embodiment 86: The radiopharmaceutical composition of Embodiments 76 to85, wherein the one or more pH stabilizers comprise an alkaline salt.Embodiment 87: The radiopharmaceutical composition of Embodiment 86,wherein the alkaline salt is sodium acetate, sodium ascorbate, sodiumbenzoate, sodium bicarbonate, sodium carbonate, tribasic sodiumphosphate acid, dibasic sodium phosphate acid, monobasic sodiumphosphate acid, sodium tartrate, sodium lactate, sodium succinate, ordisodium succinate.Embodiment 88: The radiopharmaceutical composition of Embodiments 76 to85, wherein the one or more pH stabilizers comprise an acid salt.Embodiment 89: The radiopharmaceutical composition of Embodiment 88,wherein the acid salt is ammonium sulfate.Embodiment 90: The radiopharmaceutical composition of Embodiments 76,wherein the one or more pH stabilizers comprise Sodium acetate, Sodiumascorbate, Ascorbic acid, Acetic acid, Fumaric acid propionic acid,ascorbic acid, ammonium sulfate, ammonium hydroxide, arginine, asparticacid, benzene sulfonic acid, sodium benzoate, sodium bicarbonate, boricacid, sodium carbonate, carbonic acid, diethanolamine, citrate acid,hydrobromic acid, glycine, histidine, sodium lactate, (1)-lysine, maleicacid, methane sulfonic acid, phosphate acid, monobasic sodium phosphateacid, tribasic sodium phosphate acid, dibasic sodium phosphate acid,sodium hydroxide, sodium/disodium succinate, sulfuric acid, sodiumtartrate, tartaric acid, tromethamine (tris), or a combination thereof.Embodiment 91: The radiopharmaceutical composition of Embodiments 76 to90, wherein the one or more pH stabilizers are present in theradiopharmaceutical composition at about 0.001 wt % to about 10 wt %.Embodiment 92: The radiopharmaceutical composition of Embodiment 91,wherein the one or more pH stabilizers are present in theradiopharmaceutical composition at about 0.01 wt % to about 5 wt %,about 0.05 wt % to about 2 wt %, or about 0.1 wt % to about 1 wt %.Embodiment 93: The radiopharmaceutical composition of Embodiments 76 to90, wherein the one or more pH stabilizers are present in theradiopharmaceutical composition at a concentration of from 0.1 to 5mg/mL.Embodiment 94: The radiopharmaceutical composition of Embodiments 76 to90, wherein the one or more pH stabilizers are present in theradiopharmaceutical composition at about 10 mM to about 500 mM.Embodiment 95: The radiopharmaceutical composition of Embodiments 76 to90, wherein the one or more pH stabilizers are present in theradiopharmaceutical composition at about 0.1 mM to 2 mM, 1 mM to 2 mM, 1mM to 10 mM, 5 mM to 10 mM, 5 mM to 15 mM, 1 mM to 15 mM or 1 mM to 25mM.Embodiment 96: The radiopharmaceutical composition of Embodiments 76 to95, wherein the one or more pH stabilizers are configured to maintain apH of the radiopharmaceutical composition at about 4 to about 8.Embodiment 97: The radiopharmaceutical composition of Embodiments 76 to95, wherein the one or more pH stabilizers are configured to maintain apH of the radiopharmaceutical composition at about 5 to about 7.Embodiment 98: The radiopharmaceutical composition of Embodiments 1 to95, wherein the pH of the radiopharmaceutical composition is within arange of about 4 to about 8.Embodiment 99: The radiopharmaceutical composition of Embodiments 1 to95, wherein the pH of the radiopharmaceutical composition is about 5.5to about 6.0.Embodiment 100: The radiopharmaceutical composition of Embodiments 1 to99, wherein the composition comprises one or more stabilizing agentsselected from Table 2, Table 3, and Table 4.Embodiment 101: The radiopharmaceutical composition of Embodiments 1 to100, wherein the aqueous vehicle comprises water, saline solution,dextrose in water, dextrose in saline solution, Ringer's solution, orlactated Ringer's solution.Embodiment 102: The radiopharmaceutical composition of Embodiments 1 to100, wherein the radiopharmaceutical composition is isotonic.Embodiment 103: The radiopharmaceutical composition of Embodiments 1 to102, wherein the radiopharmaceutical composition is a solution orsuspension.Embodiment 104: The radiopharmaceutical composition of Embodiments 1 to103, wherein the radiopharmaceutical composition is formulated for IVinfusion or bolus injection.Embodiment 105: The radiopharmaceutical composition of Embodiments 1 to104, wherein the radiopharmaceutical composition further comprises oneor more excipients selected from: a tonicity adjusting agent, apreservative, an antimicrobial agent, a solubilizing agent, a suspendingagent, and a surfactant.Embodiment 106: The radiopharmaceutical composition of Embodiments 24 to105, wherein the linker comprises one or more groups selected from:substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.Embodiment 107: The radiopharmaceutical composition of Embodiment 106,wherein the targeting ligand is a binding peptide, and the linker isattached to the binding peptide via the N terminus of the peptide.Embodiment 108: The radiopharmaceutical composition of Embodiment 106,wherein the targeting ligand is a binding peptide, and the linker isattached to the binding peptide via the C terminus of the peptide.Embodiment 109: The radiopharmaceutical composition of Embodiment 106,wherein the targeting ligand is a binding peptide, and the linker isattached to the binding peptide via a non-terminal amino acid of thepeptide.Embodiment 110: The radiopharmaceutical composition of Embodiments 1 to109, wherein the radionuclide is an alpha particle-emittingradionuclide.Embodiment 111: The radiopharmaceutical composition of Embodiment 110,wherein the alpha particle-emitting radionuclide is actinium-225,astatine-211, thorium-227, or radium-223.Embodiment 112: The radiopharmaceutical composition of Embodiment 110,wherein the alpha particle-emitting radionuclide is actinium-225.Embodiment 113: The radiopharmaceutical composition of Embodiment 112,wherein the actinium-225 is present in the radiopharmaceuticalcomposition that it provides a volumetric radioactivity of about 5 to 20MBq/mL.Embodiment 114: The radiopharmaceutical composition of Embodiments 1 to113, wherein the composition retains at least 90 mol % of the initialconjugate after 168 hours at room temperature (25° C.).Embodiment 115: The radiopharmaceutical composition of Embodiments 1 to113, wherein the composition retains at least 95 mol % of the initialconjugate after 168 hours at room temperature (25° C.).Embodiment 116: The radiopharmaceutical composition of Embodiments 1 to113, wherein the composition retains at least 98 mol % of the initialconjugate after 168 hours at room temperature (25° C.).Embodiment 117: The radiopharmaceutical composition of Embodiments 1 to116, wherein the composition retains at least 85 mol %, at least 90 mol%, at least 92 mol %, at least 95 mol %, at least 98 mol % or at least99 mol % of the initial conjugate after 120 hours at room temperature(25° C.).Embodiment 118: The radiopharmaceutical composition of Embodiments 1 to114, wherein the composition retains 95 mol % or more of the initialconjugate after 48 hours, 72 hours, 96 hours, 120 hours, 148 hours, 168hours, 192 hours, or 216 hours at room temperature (25° C.).Embodiment 119: The radiopharmaceutical composition of Embodiments 1 to118, wherein the radionuclide is actinium-225, and wherein thecomposition contains no more than about 5% free actinium after 168 hoursat room temperature (25° C.), compared to the total amount of theinitial chelated actinium content in the composition.Embodiment 120: The radiopharmaceutical composition of Embodiments 1 to118, wherein the radionuclide is actinium-225, and wherein thecomposition contains no more than about 2% or about 1% free actiniumafter 168 hours at room temperature (25° C.), compared to the totalamount of the initial chelated actinium content in the composition.Embodiment 121: The radiopharmaceutical composition of Embodiments 1 to120, wherein the radionuclide is actinium-225, and wherein thecomposition contains no more than a total of 5 mol % of daughterisotopes of actinium-225 after 168 hours at room temperature (25° C.),compared to the total amount of the initial chelated actinium content inthe composition.Embodiment 122: The radiopharmaceutical composition of Embodiments 1 to120, wherein the radionuclide is actinium-225, and wherein thecomposition contains no more than a total of 1 mol % of un-chelateddaughter isotopes of actinium-225 after 168 hours at room temperature(25° C.), compared to the total amount of the initial chelated actiniumcontent in the composition.Embodiment 123: The radiopharmaceutical composition of Embodiments 1 to28, comprising: (a) the conjugate, wherein the conjugate is present inthe radiopharmaceutical composition at a concentration equivalent toabout 10 to 45 mCi/L; (b) a pH stabilizer, wherein the pH stabilizer ispresent in the radiopharmaceutical composition at a concentration ofabout 80 to about 120 mM; (c) optionally a radiolysis stabilizer,wherein the radiolysis stabilizer is present in the radiopharmaceuticalcomposition at concentration of about 1 wt % to about 10 wt %; (d) afree metal chelator, therein the free metal chelator is present in theradiopharmaceutical composition at concentration of about 0.01 mg/mL toabout 1 mg/mL; and (e) an aqueous vehicle.Embodiment 124: The radiopharmaceutical composition of Embodiment 123,comprising: (a) the conjugate, wherein the conjugate is present in theradiopharmaceutical composition at a concentration equivalent to about10 to 45 mCi/L; (b) a pH stabilizer, wherein the pH stabilizer is sodiumL-ascorbate and is present in the radiopharmaceutical composition at aconcentration of about 80 to about 120 mM; (c) optionally a radiolysisstabilizer, wherein the radiolysis stabilizer is Dextran 40 and ispresent in the radiopharmaceutical composition at a concentration ofabout 1 wt % to about 10 wt %; (d) a free metal chelator, wherein thefree metal chelator is DTPA and is present in the radiopharmaceuticalcomposition at a concentration of about 0.01 mg/mL to about 1 mg/mL; and(e) an aqueous vehicle, wherein the aqueous vehicle is saline solution.Embodiment 125: The radiopharmaceutical composition of Embodiment 123 or124, comprising: (a) the conjugate, wherein the conjugate is present inthe radiopharmaceutical composition at a concentration equivalent toabout 10 to 25 mCi/L; (b) a pH stabilizer, wherein the pH stabilizer issodium L-ascorbate and is present in the radiopharmaceutical compositionat a concentration of about 90-110 mM; (c) a radiolysis stabilizer,wherein the radiolysis stabilizer is Dextran 40 and is present in theradiopharmaceutical composition at a concentration of about 4-6 wt %;(d) a free metal chelator, wherein the free metal chelator is DTPA andis present in the radiopharmaceutical composition at a concentration ofabout 0.01-0.03 mg/mL; and (e) an aqueous vehicle, wherein the aqueousvehicle is sodium chloride saline solution at a concentration of about0.9% w/w.Embodiment 126: The radiopharmaceutical composition of Embodiment 123 or124, comprising: (a) the conjugate, wherein the conjugate is present inthe radiopharmaceutical composition at a concentration equivalent toabout 10 to 25 mCi/L; (b) a pH stabilizer, wherein the pH stabilizer issodium L-ascorbate and is present in the radiopharmaceutical compositionat a concentration of about 90-110 mM; (c) a free metal chelator,wherein the free metal chelator is DTPA and is present in theradiopharmaceutical composition at a concentration of about 0.04-0.06mg/mL; and (d) an aqueous vehicle, wherein the aqueous vehicle is sodiumchloride saline solution at a concentration of about 0.9% w/w.Embodiment 127: The radiopharmaceutical composition of Embodiment 123 or124, comprising: (a) the conjugate, wherein the conjugate is present inthe radiopharmaceutical composition at a concentration equivalent toabout 25 to 35 mCi/L; (b) a pH stabilizer, wherein the pH stabilizer issodium L-ascorbate and is present in the radiopharmaceutical compositionat a concentration of about 90-110 mM; (c) a free metal chelator,wherein the free metal chelator is DTPA and is present in theradiopharmaceutical composition at a concentration of about 0.04-0.06mg/mL; and (d) an aqueous vehicle, wherein the aqueous vehicle is sodiumchloride saline solution at a concentration of about 0.9% w/w.Embodiment 128: The liquid radiopharmaceutical composition of Embodiment1, comprising or consisting essentially of: (a) the ²²⁵Ac-DOTA-TATE,wherein the ²²⁵Ac-DOTA-TATE is present in the radiopharmaceuticalcomposition at a concentration equivalent to about 10 mCi/L to about 25mCi/L; (b) the sodium ascorbate, wherein the sodium ascorbate is sodiumL-ascorbate and is present in the radiopharmaceutical composition at aconcentration of about 100 mM; (c) the DTPA, wherein the DTPA is presentin the radiopharmaceutical composition at a concentration of about 0.05mg/mL; and (d) the aqueous vehicle, wherein the aqueous vehicle issodium chloride saline solution at a concentration of about 0.9% w/w;wherein the radiopharmaceutical composition retains at least 90 mol % ofthe initial ²²⁵Ac-DOTA-TATE after stored for 120 hours at 25° C.Embodiment 129: The liquid radiopharmaceutical composition of Embodiment1, comprising or consisting essentially of: (a) the ²²⁵Ac-DOTA-TATE,wherein the ²²⁵Ac-DOTA-TATE is present in the radiopharmaceuticalcomposition in an amount of 146-275 μCi in a 12 mL solution; (b) thesodium ascorbate, wherein the sodium ascorbate is sodium L-ascorbate andis present in the radiopharmaceutical composition at a concentration ofabout 18.5 mg/mL; (c) the DTPA, wherein the DTPA is present in theradiopharmaceutical composition at a concentration of about 0.05 mg/mL;and (d) the aqueous vehicle, wherein the aqueous vehicle is sodiumchloride saline solution at a concentration of about 0.9% w/w; whereinthe radiopharmaceutical composition retains at least 90 mol % of theinitial ²²⁵Ac-DOTA-TATE after stored for 120 hours at 25° C.Embodiment 130: The liquid radiopharmaceutical composition of Embodiment1, comprising or consisting essentially of: (a) the ²²⁵Ac-DOTA-TATE,wherein the ²²⁵Ac-DOTA-TATE is present in the radiopharmaceuticalcomposition in an amount of 146-275 μCi in a 12 mL solution; (b) thesodium ascorbate, wherein the sodium ascorbate is sodium L-ascorbate andis present in the radiopharmaceutical composition at a concentration ofabout 18.5±4.63 mg/mL; (c) the DTPA, wherein the DTPA is present in theradiopharmaceutical composition at a concentration of about 0.05 mg/mL;and (d) the aqueous vehicle, wherein the aqueous vehicle is sodiumchloride saline solution at a concentration of about 0.9% w/w; whereinthe radiopharmaceutical composition retains at least 90 mol % of theinitial ²²⁵Ac-DOTA-TATE after stored for 120 hours at 25° C.Embodiment 128: A method of making a radiopharmaceutical composition ofEmbodiments 1 to 127, comprising: (a) combining a radionuclide with apre-labeled conjugate, wherein the pre-labeled conjugate comprises atargeting ligand and a metal chelator covalently attached to thetargeting ligand, thereby producing a labeled conjugate, and (b)combining the one or more stabilizing agents with the labeled conjugate.Embodiment 129: A method of making a radiopharmaceutical composition ofEmbodiments 1 to 127, comprising: (a) combining a radionuclide with apre-labeled conjugate in the presence of one or more stabilizer agents,wherein the pre-labeled conjugate comprises a targeting ligand and ametal chelator covalently attached to the targeting ligand, therebyproducing a mixture comprising a labeled conjugate, and (b) optionallycombining one or more stabilizing agents to the mixture.Embodiment 130: A method of treating a disease in a subject in needthereof, comprising administering to the subject the radiopharmaceuticalcomposition of Embodiments 1 to 127.Embodiment 131: The method of Embodiment 130, wherein the disease is acancer.Embodiment 132: The method of Embodiment 131, wherein the cancer is anSSR-associated cancer.Embodiment 133: The method of Embodiments 130 to 132, wherein the canceris an SSTR2-associated cancer.Embodiment 134: The method of Embodiments 130 to 133, wherein the canceris a neuroendocrine cancer, a lymphatic cancer, a pancreatic cancer, apituitary cancer, a breast cancer, a stomach cancer, medulloblastoma, orneuroblastoma.Embodiment 135: The method of Embodiments 130 to 134, wherein the canceris a neuroendocrine cancer.Embodiment 136: The method of Embodiment 135, comprising administeringto the subject the radiopharmaceutical composition, wherein theneuroendocrine cancer is recurrent.Embodiment 137: The method of Embodiment 134 or 135, wherein theneuroendocrine cancer is refractory to a radiotherapy that comprisesbeta-particle emitting radionuclide.Embodiment 138: The method of Embodiment 137, wherein the subject hasreceived a radiotherapy that comprises beta-particle emittingradionuclide (e.g., ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC) prior to theadministering of the radiopharmaceutical composition.Embodiment 139: The method of Embodiment 134 to 138, wherein theneuroendocrine cancer is a neuroendocrine lung cancer or aneuroendocrine pancreatic cancer.Embodiment 140: The method of Embodiment 134 to 138, wherein theneuroendocrine cancer is a Carcinoid tumor in the lungs,gastrointestinal tract or thymus, Pancreatic neuroendocrine tumor (e.g.,Gastrinoma, Insulinoma, Glucagonoma, VIPoma) Medullary thyroidcarcinoma, Merkel cell carcinoma, Pheochromocytoma of the adrenal gland,Adrenal cancer, Small cell carcinoma (such as in the lungs), or Largecell carcinoid tumor (such as in the lungs).Embodiment 141: The method of Embodiments 130 to 140, wherein theradiopharmaceutical composition is administered to the subject in anamount equivalent to about 1 kBq/kg to about 0.2 GBq/kg body weight perdose.Embodiment 142: The method of Embodiments 130 to 140, wherein theradiopharmaceutical composition is administered to the subject in anamount equivalent to about 5 kBq/kg to about 50,000 kBq/kg body weightper dose.Embodiment 143: The method of Embodiments 130 to 140, wherein theradiopharmaceutical composition is administered to the subject in anamount equivalent to about 20 kBq/kg to about 5,000 kBq/kg body weightper dose.Embodiment 144: The method of Embodiments 130 to 140, wherein theradiopharmaceutical composition is administered to the subject in anamount equivalent to about 50 kBq/kg to about 500 kBq/kg body weight perdose.Embodiment 145: The method of Embodiments 130 to 140, wherein theradiopharmaceutical composition is administered to the subject in anamount equivalent to about 50 kBq/kg to about 200 kBq/kg body weight perdose.Embodiment 146: The method of Embodiments 130 to 140, comprisingadministering to the subject the radiopharmaceutical composition whereinthe radiopharmaceutical composition is administered to the subject in anamount equivalent to about 70 kBq/kg to about 150 kBq/kg body weight perdose.Embodiment 147: The method of Embodiments 130 to 146, comprisingadministering to the subject the radiopharmaceutical composition,wherein the radiopharmaceutical composition is administered at an 8-weekinterval.Embodiment 148: The method of Embodiments 130 to 147, comprisingadministering to the subject the radiopharmaceutical composition,wherein the radiopharmaceutical composition is administered to achieve acumulative dose in the subject of about 10,000 kBq to about 100,000 kBq.Embodiment 149: The method of Embodiments 130 to 147, comprisingadministering to the subject the radiopharmaceutical composition,wherein the radiopharmaceutical composition is administered to achieve acumulative dose in the subject of about 40,000 kBq to about 70,000 kBq.

We claim:
 1. A liquid radiopharmaceutical composition consisting of: (a)²²⁵Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof, whereinthe ²²⁵Ac-DOTA-TATE or the pharmaceutically acceptable salt thereof ispresent in the radiopharmaceutical composition at a concentrationequivalent to about 10 mCi/L to about 30 mCi/L; (b) sodium L-ascorbate,wherein the sodium L-ascorbate is present in the radiopharmaceuticalcomposition at a concentration of about 90 mM to about 110 mM; (c)diethylenetriamine pentaacetate (DTPA), wherein the DTPA is present inthe radiopharmaceutical composition at a concentration of about 0.04mg/mL to about 0.06 mg/mL; (d) an aqueous vehicle, wherein the aqueousvehicle is sodium chloride saline solution at a concentration of about0.9% w/w; and (e) a sodium acetate buffer; wherein theradiopharmaceutical composition is a solution, and wherein theradiopharmaceutical composition retains at least 90% of the ²²⁵Accontent as ‘Ac-DOTA-TATE or the pharmaceutically acceptable salt thereofafter 120 hours at about 20° C. to about 25° C. as determined by radiothin-layer chromatography (radio-TLC).
 2. The liquid radiopharmaceuticalcomposition of claim 1, wherein the ²²⁵Ac-DOTA-TATE or thepharmaceutically acceptable salt thereof is present in theradiopharmaceutical composition at a concentration equivalent to about10 mCi/L to about 25 mCi/L.
 3. The liquid radiopharmaceuticalcomposition of claim 1, wherein the ²²⁵Ac-DOTA-TATE or thepharmaceutically acceptable salt thereof is present in theradiopharmaceutical composition at a concentration equivalent to about12 mCi/L to 23 mCi/L.
 4. The liquid radiopharmaceutical composition ofclaim 1, wherein the ²²⁵Ac-DOTA-TATE or the pharmaceutically acceptablesalt thereof is present in the radiopharmaceutical composition at aconcentration equivalent to about 40 μg to about 120 μg of theDOTA-TATE.
 5. The liquid radiopharmaceutical composition of claim 1,wherein the sodium L-ascorbate is present in the radiopharmaceuticalcomposition at a concentration of about 100mM.
 6. The liquidradiopharmaceutical composition of claim 1, wherein the DTPA is presentin the radiopharmaceutical composition at a concentration of about0.05mg/mL.
 7. The liquid radiopharmaceutical composition of claim 1,wherein the composition retains at least 90% of the ²²⁵Ac content as²²⁵Ac-DOTA-TATE or the pharmaceutically acceptable salt thereof after168 hours at about 20° C. to about 25° C.
 8. The liquidradiopharmaceutical composition of claim 1, wherein the compositionretains at least 90% of the ²²⁵Ac content as ²²⁵Ac-DOTA-TATE or thepharmaceutically acceptable salt thereof after 192 hours at about 20° C.to about 25° C.
 9. The liquid radiopharmaceutical composition of claim1, wherein the radiopharmaceutical composition is formulated as a unitdose form that contains about 12mL of the solution.
 10. The liquidradiopharmaceutical composition of claim 1, consisting of: (a)²²⁵Ac-DOTA-TATE or the pharmaceutically acceptable salt thereof presentin the radiopharmaceutical composition at a concentration equivalent to10 mCi/L to 25 mCi/L; (b) sodium L-ascorbate present in theradiopharmaceutical composition at a concentration of about 100 mM; (c)DTPA present in the radiopharmaceutical composition at a concentrationof about 0.05 mg/mL; (d) sodium chloride saline solution at aconcentration of about 0.9% w/w; and (e) a sodium acetate buffer. 11.The liquid radiopharmaceutical composition of claim 1, wherein theliquid radiopharmaceutical composition is formulated as a unit dose formthat has about 12mL of the solution, and wherein the liquidradiopharmaceutical composition consists of : (a) ²²⁵Ac-DOTA-TATE or thepharmaceutically acceptable salt thereof present in theradiopharmaceutical composition in an amount of 146-275 μCi in the about12 mL solution; (b) sodium L-ascorbate present in theradiopharmaceutical composition at a concentration of about 18.5 mg/mL;(c) DTPA present in the radiopharmaceutical composition at aconcentration of about 0.05 mg/mL; (d) sodium chloride saline solutionat a concentration of about 0.9% w/w; and (e) a sodium acetate buffer.12. The liquid radiopharmaceutical composition of claim 1, wherein a pHof the liquid radiopharmaceutical composition is about 5.5 to about 7.0.13. The liquid radiopharmaceutical composition of claim 1, wherein theradiopharmaceutical composition is formulated for IV infusion.
 14. Theliquid radiopharmaceutical composition of claim 1, wherein the²²⁵Ac-DOTA-TATE or the pharmaceutically acceptable salt thereof has astructure illustrated as